Seminar
Haemolytic uraemic syndrome
Lancet 2022; 400: 1722–40
Published Online
October 19, 2022
https://doi.org/10.1016/
S0140-6736(22)01202-8
Division of Pediatric
Nephrology, Baylor College of
Medicine, Texas Children’s
Hospital, Houston, TX, USA
(M Michael MD); Department of
Pediatrics, All India Institute of
Medical Sciences,
New Delhi, India
(Prof A Bagga MD);
Pediatrics-Hematology/
Oncology, Baylor College of
Medicine, Houston, TX, USA
(S E Sartain MD); Department of
Otolaryngology, Pediatrics and
Molecular Physiology &
Biophysics, The University of
Iowa, Iowa City, IA, USA
(Prof R J H Smith MD)
Correspondence to:
Dr Mini Michael, Division of
Pediatric Nephrology,
Baylor College of Medicine,
Texas Children’s Hospital,
Houston, TX 77030, USA
mmichael@bcm.edu
1722
Mini Michael, Arvind Bagga, Sarah E Sartain, Richard J H Smith
Haemolytic uraemic syndrome (HUS) is a heterogeneous group of diseases that result in a common pathology, thrombotic
microangiopathy, which is classically characterised by the triad of non-immune microangiopathic haemolytic anaemia,
thrombocytopenia, and acute kidney injury. In this Seminar, different causes of HUS are discussed, the most common
being Shiga toxin-producing Escherichia coli HUS. Identifying the underlying thrombotic microangiopathy trigger can be
challenging but is imperative if patients are to receive personalised disease-specific treatment. The quintessential example
is complement-mediated HUS, which once carried an extremely high mortality but is now treated with anti-complement
therapies with excellent long-term outcomes. Unfortunately, the high cost of anti-complement therapies all but precludes
their use in low-income countries. For many other forms of HUS, targeted therapies are yet to be identified.
Introduction purpura from HUS through the use of PLASMIC or
Haemolytic uraemic syndrome (HUS), comprising non- French scores is recommended by the International
immune microangiopathic haemolytic anaemia, throm­bo­ Society on Thrombosis and Haemostasis.4 Since
cytopenia, and acute kidney injury, is associated with thrombotic thrombocytopenic purpura is a distinct disease
substantial acute and chronic morbidity in children and entity, its further discussion is beyond the scope of this
adults. The unifying feature of this heterogeneous group Seminar. This Seminar focuses on the epidemiology,
of diseases is endothelial damage, which leads to the pathophysiology, genetics, and clinical manifestations of
formation of microthrombi in vascular beds in multiple various types of HUS, and discusses approaches to their
organs, thrombocytopenia due to platelet consumption, diagnosis and treatment.
and haemolysis caused by intravascular mechanical
disruption of erythrocytes traversing the microthrombotic Classification and pathology
fibrin network.1–3 Treatment for HUS is varied and depends The classification of HUS is challenging and constantly
on the underlying cause. Its early recognition is important, evolving. An aetiology-based classification is often used
both for comprehensive evaluation of the cause, and to (figure 1). Infection-associated HUS includes that
allow timely intervention with specific, effective treatment second­ ary to Shiga toxin-producing Escherichia coli
when applicable. Age at presentation, clinical symptoms, (STEC), Streptococcus pneumoniae, and H1N1/influenza
and family history are important in the initial evaluation. A. Atypical HUS (aHUS) is broadly used for all other
Although thrombotic thrombocytopenic purpura can types, which can be primary or secondary. Primary aHUS
present with similar features, making it difficult to typically denotes the presence of an underlying
distinguish from HUS, the underlying cause differs. complement system defect (such as a mutation in a
Thrombotic thrombocytopenic purpura develops complement gene or the presence of factor H [FH]
secondary to acquired or congenital deficiency of von autoantibodies), as well as other causes such as
Willebrand protease, ADAMTS13 (a disintegrin and metabolism-associated HUS (cobalamin C disease), and
metalloproteinase with thrombospondin type 1 motifs, DGKE and WT1-associated HUS. The term secondary
member 13). Distin­ction of thrombotic thrombocytopenic HUS implies another underlying cause for disease, such
as infection, malignant hypertension, or complement-
amplifying conditions such as systemic lupus
Search strategy and selection criteria erythematosus, scleroderma, and anti­ phospholipid
We searched the Cochrane Library, MEDLINE, and Embase syndrome. Secondary HUS can also be associated with
between Jan 1, 2010, and April 30, 2021. We used the search co-existing conditions such as pregnancy, the use of
terms “haemolytic uremic syndrome”, “thrombotic particular drugs such as calcineurin inhibitors, oral
microangiopathy”, “shigatoxin”, “pneumococcus”, “factor H contraceptives, and quinine, malignancy, and stem-cell
autoantibody”, “drug induced TMA”, “transplant”, and solid organ transplantation. This primary versus
“WT1 mutation”, “DEGKE mutation”, “eculizumab”, secondary binary classification belies the fact that, even
and “ravulizumab” in combination with the terms in the presence of a complement abnormality, an
“pathophysiology”, “causes” and “treatment”. We largely initiating trigger (eg, infection) is the rule rather than the
selected publications from within the past 5 years but did not exception, and underscores the challenge associated with
exclude commonly referenced and highly regarded older determining the underlying cause of disease, which is
publications. We also searched the reference lists of articles clinically relevant because prompt treatment with a
identified by this search strategy and selected those we terminal complement inhibitor improves renal outcomes
judged relevant. Review articles and book chapters are cited of complement-driven aHUS.5–7 Because the response is
to provide readers with more details and more references dramatic and potentially life-saving, anti-comple­ment
than this Seminar has space for. therapy is often started immediately, and discon­tinued if
a non-complement cause for disease is later identified.
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 Seminar

Pathological findings in HUS (appendix p 20) reflect
tissue responses to endothelial injury, including
endothelial swelling, subendothelial widening, and
presence of luminal fibrin with entrapped fragmented
red cells; substantial luminal occlusion in glomerular
capillaries and arterioles can occur (figure 1). Ultra­
structural evaluation shows glomerular endothelial
swelling, fenestral fusion, subendothelial expansion with
electron-lucent material, and later reduplication of the
glomerular basement membrane (figure 2).
Infection-associated HUS
Shiga toxin-associated HUS
Incidence and epidemiology
The most common infectious agent that causes HUS,
especially in children younger than 5 years of age, is
STEC. Rarely, other Shiga toxin-producing bacteria
including Shigella dysenteriae, Shigella flexneri,
Shigella sonnei and Citrobacter spp are isolated. STEC is a
water-borne and food-borne pathogen that causes
diarrhoea and haemorrhagic colitis.8 Diarrhoea or
dysentery due to Shiga toxin-producing enteropathogens
is followed by HUS in 5–15% of cases, a proportion that
can reach 20–30% during outbreaks. The predominant
STEC serotype causing HUS is O157:H7, responsible for
around 2000 such cases annually worldwide.9,10 The most
common non-O157 serogroups in Europe include
O145, O146, O91, O103, and O26, and in the USA,
O121, O45, O26, O111, O103, and O145.11 The non-O157
organisms are a heterogeneous group with variable
HUS risk (around 1%) and are more commonly
encountered in patients with diarrhoea or dysentery. 12
STEC-HUS is mostly sporadic, the incidence being
highest in young children.13 The reason for its lower
incidence in adults might be due to the acquired
presence of anti-Shiga toxin (Stx) antibodies or to higher
glomerular expression of the globotriaosylceramide
3 (Gb3) Stx receptor in children. STEC colonise cattle
and transmission is faecal-to-oral via undercooked
contaminated beef, raw milk products, drinking water,
direct contact with animals, and person-
to-person spread. Contamination of leafy vegetables is
an important cause of STEC infection. 14 The
2011 German epidemic, caused by the O104:H4 serotype,
was unique for several reasons: an enteroaggregative
E coli that acquired a prophage-encoding Stx2 was
responsible, mostly adults were affected, the typical
history of dysentery was absent, and HUS occurred
in 20–22% of patients with frequent neurological
complications and high mortality (54 deaths in nearly
4000 people infected).15 The STEC O80:H2 serotype that
emerged in France and Switzerland was associated with
severe HUS,16 while the recurrent outbreaks of
diarrhoeal infection in England in 2014–18 were
associated with STEC O55:H7, with early age at onset
(median 4 years [range 6 months–69 years]) and HUS in
54% of patients. 17
Pathogenesis See Online for appendix
STEC produce two main types of Shiga toxins (Stx) known
as Stx1 and Stx2, encoded by the stx1 and stx2 genes. Stx is
composed of a single A subunit (30 kDa) and five B subunits
(each 7 kDa); the former is biologically active and the latter
binds to the cell surface receptor. The majority of STEC
O157 harbour stx2. 9,18 Stx2 is regarded as more virulent
than Stx1, with higher risk of causing HUS. The
mechanism of cytotoxicity and complement activation by
Stx is shown in the appendix (pp 18–20). Stx produced by
bacterial infection of the large intestine binds the
enterocyte, and crosses the brush border to enter the
circulation. The pentameric B subunit of the toxin binds to
Gb3 and TLR4 expressed on circulating blood cells, causing
activation of neutrophils, monocytes, platelets, and
erythrocytes, inducing budding of microvesicles containing
the toxin within and on its surface. Micro­ vesicles are
endowed with activated complement factors C3b and C9
and tissue factor. The key pathogenic mechanism in STEC-
HUS is targeting by Stx or Stx associated with microvesicles
to Gb3-expressing endothelial cells, followed by docking
and release of toxin by microvesicles. The A1 subunit of the
toxin causes depurination of adenosine in a highly
conserved region of the 28s ribosomal subunit of 60s
ribosomal RNA that alters its binding to tRNA, interrupting
the synthesis of proteins and leading to cell death.19,20 Other
mechanisms of cytotoxicity include increased synthesis of
chemokines (via the SDF-1–CXCR4–CXCR7 pathway) and
adhesion molecules. Stx induces surface mobilisation of
P-selectin that favours C3 activation and the assembly of
Infection-associated HUS Complement-mediated aHUS
Shiga toxin-producing Hereditary: mutations of CFH,
Escherichia coli HUS CFI, C3, CFB, MCP and THBD
Streptococcus pneumoniae Acquired: factor H
H1N1/influenza A autoantibody-associated HUS
Non-complement-
mediated aHUS
DGKE
Pregnancy-induced aHUS
WT1
G6PD
Metabolism-associated
HUS
Drug-induced aHUS
Cobalamin C disease
Methionine synthase
deficiency
Coagulation-mediated aHUS
Transplant-associated HUS Thrombomodulin
Haematopoietic stem cell transplantation
thrombotic microangiopathy Secondary aHUS
Solid organ transplantation thrombotic Malignant hypertension
microangiopathy Complement-amplifying conditions
Antiphospholipid antibody
Malignancy or cancer
Figure 1: Aetiology-based classification of HUS
The centre circle shows light microscopy of renal biopsy findings of thrombotic microangiopathy: glomerular fresh
fibrin thrombus (green arrow) with severe red blood cell congestion (haematoxylin and eosin stain
20 × magnification). HUS=haemolytic uraemic syndrome. aHUS=atypical haemolytic uraemic syndrome.

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 Seminar

ulcers on colonoscopy. Severe colonic involvement can

Neurological result in complications such as toxic megacolon and
Seizures, nystagmus, diplopia, hemiparesis,
headache, altered consciousness,
transmural necrosis with gastrointestinal perforation or
hallucinations, encephalopathy, and coma right-sided colonic strictures. After a median of 7 days,
when diarrhoea is resolving, around 5–15% of patients
develop HUS. The risk factors for developing HUS include
age younger than 5 years, high white blood cell count,
Ocular Gastrointestinal specific strains of STEC (O157:H7, O126, and O104:H4),
Loss of visual acuity, visual Diarrhoea, vomiting, and infection with organisms producing Stx2.27 Features of
scotomas, ocular pain, pancreatitis, cholelithiasis,
diplopia, and blurred transaminitis, hepatitis, HUS include fatigue, pallor, and oligoanuria, with or
vision and gastrointestinal without fluid overload, hypertension, and oedema. Most
bleeding
patients have mild disease, managed by optimised fluid
balance, nutrition support, and control of hypertension.
Dialysis is required in 30–60% of patients with severe
illness and oligoanuria. A proportion of patients (about
Cardiac 70%) require transfusion of red cells. Case series suggest
Pulmonary Left ventricular hypertrophy, that almost all adult patients have loose stools, and bloody
Pulmonary oedema, pulmonary hypertrophic cardiomyopathy,
haemorrhage, and pulmonary dilated cardiomyopathy, elevated diarrhoea is relatively less frequent than in children.28,29
embolism creatine kinase blood level, valve Cerebral involvement characterised by irritability,
insufficiency and intracardiac
thrombus
altered consciousness, and seizures, is seen in 10–25% of
cases.30,31 Other characteristics include pyramidal and
Figure 2: Extra-renal manifestations of atypical haemolytic uraemic syndrome extrapyramidal features, diplopia, dysphasia, and facial
The centre circle shows electron microscopy of renal biopsy findings of thrombotic microangiopathy: endothelial nerve palsy. Severe neurological involvement, mainly in
swelling (green star), fenestral fusion, and subendothelial expansion with reduplication of the glomerular the form of persistent encephalopathy, brain haemorrhage
basement membrane (green arrow) are considered evidence of endothelial injury (uranyl acetate and lead citrate, or infarction, and anoxic brain injury, is associated with
830 × magnification).
worse disease severity and higher mortality.32,33 The
neurological outcomes are satisfactory, with most patients
alternative pathway C3 convertase (C3bBb) on the cell showing complete recovery.31 Neurological findings are
surface. The anaphylatoxin C3a interacts with its more common in adults than in children.29
endothelial receptor (C3aR), potentiating P-selectin Pancreatic involvement with elevated blood levels of
expression and throm­bomodulin shedding with thrombus amylase and lipase may be seen in up to two-thirds of
formation. Shiga­toxin also binds ultra-large multimers of patients with STEC-HUS during the acute phase. Throm­
von Willebrand factor and reduces their cleavage by botic microangiopathy (TMA) might involve both the
ADAMTS13 which leads to further thrombosis. Elevated endocrine and exocrine pancreas; pancreatic inflammation
free haemoglobin concentrations during haemolysis with TMA and pancreatic necrosis has rarely been reported.34
further mediate endothelial injury by promoting oxidative A meta-analysis, including 1139 patients from 13 studies,
stress and a pro-thrombotic state. There is growing showed that the pooled incidence of diabetes during the
evidence of alternative complement pathway activation in acute stage of HUS was 3·2% (95% CI 1·3–5·1).35
STEC-HUS, with some patients demonstrating comple­ Later onset (3–6 months) of diabetes has also been
ment cleavage products, soluble C5b-9 (sC5b-9), and reported. Cardiovascular involvement with hypertension,
comple­ment-coated micro­vesicles.21–23 In vitro, Stx binds to congestive heart failure, pericardial effusion, depressed
short consensus repeats 6–8 and 18–20 of FH, impairing its myocardial function, and left ventricular hypertrophy is
complement regulatory effect. Children with STEC-HUS reported in children with STEC-HUS.32 In a case series,
and reduced levels of C3 are at risk for neurological 19 of 64 patients with STEC-HUS undergoing autopsy had
involvement and severe clinical mani­ festations.24 The cardiac involvement, including 15 with TMA affecting
patho­ genesis of neurological findings is unclear, and myocardial vessels, and two each with multiple haemorr­h­
includes the combination of Stx-induced vascular injury ages without TMA, and left ventricular infarction.36
and endothelial dysfunction, inflammation of neural cells
due to cytokine release, and direct binding of Stx to neural S pneumoniae-associated HUS
cells.25,26 Epidemiology
S pneumoniae-associated HUS (Sp-HUS), comprising
Clinical features 5% of all cases of HUS, is a serious complication of
Profuse bloody diarrhoea (haemorrhagic colitis) occurs in invasive pneumococcal disease.37,38 The incidence of
about 90% of patients around 3–8 days after ingestion of HUS after invasive pneumococcal disease is 0·4–0·6%,
contaminated food. Abdominal pain is substantial and but it is possibly underdiagnosed because no clear case
defecation is painful. Inflammation mainly affects the right definition or specific laboratory test exist, and it can be
colon, with notable oedema, easy bleeding, and longitudinal misdiagnosed as pneumococcal sepsis or disseminated

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intravascular coagulation39,40 (appendix p 2). 41,42 A public
health surveillance study in the UK from 2006 to 2016
reported a reduction in the incidence of Sp-HUS
from 0·25 per 100 000 to 0·08 per 100 000 during that
time period associated with change in the pneumococcal
conjugate vaccine from the seven-valent vaccine to the
13-valent vaccine.43 Serotype 19A was most commonly
associated with HUS, probably due to enhanced
expression of neuraminidase in the serotype.
Pathophysiology
Pneumococcal neuraminidase cleaves terminal N-acetyl
neuraminic acid (sialic acid) from glycoproteins present
on erythrocytes, glomerular endothelial cells, renal
epithelial cells and platelets, exposing the normally
hidden Thomsen-Friedenreich (T) antigen44 (appendix
pp 17–20). Preformed IgM antibodies react to exposed
T antigen on these cells, with initiation of a cascade of
events resulting in Sp-HUS.44,45 A heavy bacterial load
leads to increased production of neura­minidase (which
cleaves glycosidic linkages of neuraminic acid), making
Sp-HUS more likely. It has been hypothesised that
complement plays a role in the development of Sp-HUS,
although the precise mechanisms are not understood.
Two recent studies identified genetic defects of comple­
ment proteins that might be responsible for Sp-HUS,46,47
while another study postulated that the loss of cell-
surface binding sites for FH occurs secondary to
desialylation. Some pneumococcal serotypes (serotypes
2 and 3) directly bind to FH and inhibit its action,
thereby leading to acquired dysregulation of
complement.48,49
Definition and diagnosis
In 2002, the Canadian Pediatric Surveillance Program
classified patients with invasive pneumococcal infection
and features of HUS into definite and possible cases
(appendix p 3). Renal biopsy is usually not required for the
diagnostic workup. Many experts use the peanut lectin
agglutination and direct Coombs tests as evidence of
T antigen activation to define Sp-HUS.41,42,50,51 Coagulation
studies to rule out disseminated intravascular coagulation
are also included in the definitions.41,51 Invasive pneumo­
coccal infection is diagnosed on culture, antigen detection,
or positive PCR from blood or physiologically sterile
biological fluid.
A modified Sp-HUS case definition41,42 is shown in the
appendix (p 3). Demonstration of T antigen presence by
peanut agglutinin test is 86% sensitive and 57% specific
for Sp-HUS or pneumococcal haemolytic anaemia, and
has a positive predictive value of 76%.52 Since T antigen
is activated before the drop in haemoglobin or platelets,
use of the peanut agglutinin test is recommended as
soon as invasive pneumococcal disease is suspected.
Although the positivity of direct Coombs test among
children with Sp-HUS varies, it has been reported to be
positive in up to 90% of patients.39,48 A positive Coombs
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Seminar
test in patients with invasive pneumococcal infection
seems to be sensitive for Sp-HUS, but its specificity is
unclear.
Clinical features
Compared with those affected by STEC-HUS, children
affected by Sp-HUS are younger (aged <2 years) with severe
renal or haematological disease or both, have a longer stay
in hospital, and are more likely to have persistent kidney
dysfunction due to cortical necrosis41,53,54 (appendix p 2).
Approximately 25% of patients have extrarenal
complications, including impaired liver function.54
Other infectious causes of HUS
Other infectious causes of HUS have been well studied
and reported in the literature. The pathogenesis of
infectious disease-associated HUS is complex, and
includes direct endothelial injury and complement
activation.55 The list of infectious causes is long and
includes H1N1 influenza (production of neuraminidase
similar to Sp-HUS), HIV, cytomegalovirus, Epstein-Barr
virus, varicella zoster virus, parvovirus B19, malaria, and
dengue fever. Microvascular injury and TMA have also
been reported with SARS-CoV2 infection, due to its
direct effect on endothelial cells and complement
activation.56
Primary aHUS or complement-mediated HUS
Epidemiology
aHUS is an ultra-rare disease with an estimated annual
incidence in the USA of around two cases per 1 000 000.37
aHUS can occur at any age but onset during childhood is
more frequent than in adulthood and accounts for
approximately 10% of cases in children, but most HUS
cases in adults. Autoantibodies to FH are responsible for
about 10% of cases of complement-mediated aHUS.3
This type of HUS is often referred to as DEAP-HUS
(deficiency of FHR1 plasma protein and anti-FH positive
HUS; appendix p 12).57
Pathophysiology
The pathophysiological consequences of aHUS result
directly from damage due to uncontrolled activation of
the alternative complement pathway. 58–60 A link between
complement and aHUS was first reported in 1981 in two
brothers who had deficiency of FH; later, in 1998,
mutations in CFH were recognised to be associated with
aHUS.61,62 Since then, mutations in several other
complement genes have been identified.63 The alternative
pathway is most commonly implicated. A unique feature
of this pathway is its continuous low-level spontaneous
activation through a process of C3 hydrolysis known as
tick-over. Tick-over drives the production of low levels of
C3 convertase (C3bBb) and if complement is further
activated, C5 convertase (C3bBbC3b) forms. C5 convertase
cleaves C5 to generate C5b, which binds to C6, C7, C8, and
multimers of C9 to produce C5b-9, the membrane attack
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complex. As early as 30 min after assembly of the
membrane attack complex, cell lysis occurs.
Complement damage to self-surfaces is prevented by
regulators of complement activation (RCA) proteins.64,65
The major RCA proteins in the pathogenesis of aHUS are
FH, factor I (FI), and membrane cofactor protein (MCP,
CD46; table 1). Dysregulation of the alternative pathway
can arise from loss-of-function mutations in the genes
that encode these proteins or from hybrid genes that
encode FHR1–FH fusion proteins.71 Cross-talk between
the coagulation system and the complement cascade also
occurs and is important to the disease process72 (appendix
pp 18–19). Complement activation occurs in a sequential
manner by initiation of complement activation, formation
and amplification of C3 convertase (C3bBb), formation
and amplification of C5 convertase (C3bBbC3b), and the
assembly of the terminal complement complex or MAC
(C5b-9). The self-amplifying process of the alternative
pathway is inhibited by multiple regulator molecules.
FH is a fluid-phase inhibitor of the C3 convertase
and competes with factor B for binding to C3b
and displaces Bb from the C3bBb convertase (decay-
accelerating activity). It acts as a cofactor for FI in the
cleavage of C3b to iC3b. Three membrane glycoproteins,
C3b receptor (CR1, CD35), MCP (CD46), and decay
accelerating factor (CD55), act as inhibitors of C3 and
C5 convertases, whereas protectin (CD59) inhibits the
assembly of the MAC. CR1 and delay-accelerating factor
have decay-accelerating activity towards C3 and
C5 convertases. CR1 and MCP act as cofactors for
complement factor I-mediated cleavage of C3b. Clusterin
and vitronectin are plasma proteins that prevent the
insertion of terminal complement complexes into cell
membranes. The activity of the alternative pathway
C3/C5 convertase can be enhanced by the only known
physiological positive complement regulator, properdin.
Genetics
Approximately 60% of patients with aHUS carry a
mutation in a gene encoding a protein essential for
alternative pathway function. Mutations in CFH are
most frequently identified and account for 25–30% of
cases.66,67 These mutations either reduce production of
FH, result in a null allele, or generate a protein with
abnormal functionality. Most missense mutations that
impair FH function occur at the C-terminal region
of the protein, a site essential for attachment to
cell membranes and protection of host cells from
complement-mediated damage.60,73 Fusion proteins,
which include FH/FHR1, FH/FHR3 and FHR1/FH
fusions, act as competitive antagonists of FH and also
lead to complement dysregulation at the cell surface.71,74
MCP mutations are reported in about 9% of patients
with aHUS and lead to decreased expression of MCP on
cell surfaces or impaired regulation of complement.68,75
Mutations in CFI are reported in around 8% of patients.
Less frequent are the gain-of-function mutations in
C3 (2–8%) and CFB (1–4%), both of which increase

Protein function Frequency End-stage renal disease in native kidney after first presentation or Risk of recurrence
of at 1 year in transplant
mutation kidney
French registry Italian registry* American Global registry
registry†
CFH Inhibits C3b binding, inhibits 20–30% Children: 47%; 31% 41% Children: 42%; 80–90%
production and accelerates decay adults: 58% (41% unknown) adults: 42%
of C3 convertase; cofactor for FI
MCP Cofactor for FI to cleave C3b and 10–15% Children: 0%; 6% 14% Children: 0%; 15–20%
C4b on surface of host cells adults: 63% (57% unknown) adults: 0%
C3 Generates C3a and 5–10% Children: 43%; 58% Unknown Children: 25%; 40–50%
C3b, constituents of adults: 63% adults: 11%
C3 convertase and C5 convertase
CFB Binds to C3 and forms C3 1–4% NA NA 33% NA 100%
convertase (14% unknown)
CFI Cleaves and inactivates C3b and 4–10% Children: 17%; 60% 33% Children: 0%; 70–80%
C4b in the presence of cofactors adults: 42% (33% unknown) adults: 33%
FH, MCP, and THBD
THBD Regulate FI-induced 3–5% NA 15% 25% NA Not reported
C3b inactivation (25% unknown)
Combined Depends on the combination of 2–12% NA NA 71% NA Combined CFH
mutation proteins affected (29% unknown) and MCP risk
haplotype: 30%
FHAA Affects FH function 4–6% NA 37% NA Children: 28%; High, if antibody
adults: 10% titre is high
FH=factor H. FHAA=factor H autoantibody. FI=factor I. MCP=membrane cofactor protein. NA=not available. THBD=thrombomodulin. *Overall outcome and was not
reported separately in children and adults. †Overall outcome; in many patients the outcome was unknown.

Table 1: Role of complement regulatory proteins and their mutation in atypical HUS66–70

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alternative complement pathway activity. Thrombo­
modulin is a cofactor in the initiation of the protein C
anticoagulant pathway and also accelerates the inactivation
of C3b by FI. In-vitro studies have shown that THBD
mutations result in dysregulation of the complement
system.76 About 12% of patients carry mutations in two or
more genes implicated in aHUS.
Although familial disease (autosomal recessive or
dominant inheritance) is observed in about 20% of
families,67,77 the absence of a positive family history
does not preclude the possibility of genetic trans­
mission. Most aHUS-associated complement mutations
segregate as heterozygous variants, meaning that the
mutation will be found in a parent. Penetrance is highly
variable and approximates 50%. Factors that impact
penetrance include age, specific triggers (eg, infection or
pregnancy), genetic burden (other gene variants) and
circulating levels of regulatory proteins (especially FH),
under­scoring the fact that aHUS is a multifactorial disease
that results from environmental events that initiate
endothelial damage and genetic factors (mutations and at-
risk polymorphisms) that affect disease progression.
Clinical features
Most patients with aHUS present acutely with the
triad of TMA with non-immune haemolytic anaemia,
thrombocytopenia, and kidney dysfunct­ ion follow­ ing a
triggering event. Less commonly, patients have indolent
disease, with subclinical anae­mia, fluctuating throm­bo­
cytopenia, preserved kidney function, and non-s­ pecific
symptoms such as malaise, fatigue, and anorexia, making
diagnosis difficult. aHUS renal manifes­tations are variable
and include acute kidney injury, nephrotic range
proteinuria resulting from glomerular basement
membrane damage, and hyper­tensive emergency. Patients
with hypertensive emergency at presentation have poor
kidney outcomes and a high incidence of progressive
kidney disease.78
Extrarenal manifestations occur in around 20% of
patients with aHUS, with the incidence of specific organ
system complications ranging from a few case reports to
50% of described patients (figure 2). Such complications
can occur not only during the acute phase of aHUS, but
also later.66,79–81 Neurological symptoms are reported in
8–48% of cases: seizures can occur in the acute phase both
in the presence and absence of hypertension. MRI changes
can help to distinguish between posterior reversible
encepha­­lopathy syndrome with hypertension versus TMA-
specific findings, which include hyper i­ntense lesions in
the posterior white matter, posterior cortex, deep white
matter, thalami, brainstem, and basal ganglia. Ocular
involvement can be serious but is rare; reported ocular
findings on fundoscopic examination include bilateral
flame-shaped intraretinal haemorrhage, optic disc oedema,
central retinal vein occlusions, and tortuosity of the retinal
vessels. Full recovery after initiation of therapy with
eculizumab has been reported in some patients, whereas
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others can have persistent visual deficits. Cardiac
manifestations are identified in 7% of paediatric patients
with aHUS.79 In some patients with aHUS, hypertension
and fluid overload associated with acute kidney injury can
lead to cardiac dysfunction, but there are also reports of
cardiac symptoms independent of these factors, suggesting
direct injury to the myocardial tissue and vasculature.82
Peripheral vascular manifestations with skin changes,
including cutaneous rash and peripheral gangrene, have
been described in a few reported aHUS cases.83–85 Skin
changes can occur in the absence of anaemia or
thrombocytopenia, and therefore might be evidence of
persistent comple­ment activation in the absence of other
biochemical abnormalities typically associated with aHUS.
Gastro­intestinal manifestations can also occur: analysis of
global registry of aHUS data by Schaefer and colleagues69
reported gastrointestinal manifestations in a greater
proportion of paediatric patients (47%) than adults (33%)
in the acute phase. However, only 10% of paediatric
patients experienced gastrointestinal symptoms in a
Turkish registry study.86 Pulmonary mani­festations were
seen in a lower proportion of pediatric patients (12%) than
adult patients (20%) in the global registry of aHUS.69
Careful monitoring of fluid and respiratory status is
needed in patients with aHUS because respiratory
failure secondary to pulmonary oedema necessitating
mechanical ventilation is a serious and life-threating
complication.
Non-complement-mediated aHUS
Non-complement-mediated aHUS, including that caused
by DGKE and WT1 mutations, should be considered
when disease presentation occurs early, typically within
the first 12 months of life, and also in patients who are
resistant to complement inhibitor therapy (panel 1 and
appendix p 18). G6PD deficiency, an X-linked recessive
disease due to mutations in G6PD, can in rare cases
mimic the diagnosis of HUS.101,102
Metabolism-associated HUS
The differential diagnosis of HUS includes metabolism-
associated conditions, the most common being cobala­min
C deficiency, an inborn error of vitamin B12 metabolism.
Cobalamin G deficiency is less common but also
can present as a TMA. Inherited as an autosomal recessive
disorder, cobalamin C disease is caused by mutations in
MMACHC, whereas cobalamin G is due to a mutation in
MTR. Notwith­­s­tanding their rarity, these diagnoses are
important to make because targeted disease-specific
therapy is available, and therapy with eculizumab is not
effective. The pathophysiology, clinical features, and
management of metabolism-associated HUS are
discussed in panel 2, figure 3, and the appendix (p 19).
Transplant-associated HUS
HUS can occur after haematopoietic stem cell
transplantation (HSCT) or, less commonly, after solid
1727
 Seminar
Panel 1: Clinical characteristics of HUS due to non-complement causes
DGKE mutation-associated HUS
• Epidemiology and pathophysiology
• DGKE-mediated disease is exceedingly rare (0·009 cases
per million per year)87
• Inherited as an autosomal recessive disease (homozygous or
compound heterozygous mutations)
• DGKE encodes diacylglycerol kinase-epsilon (DGKε), an
intracellular lipid kinase with high specificity for
diacylglycerol conjugated with arachidonic acid in the
absence of DGKε; a shortage of phosphatidyl inositol
bisphosphate compromises VEGFR2-dependent protein
kinase B (Akt) activation, perturbing the complex autocrine
signalling pathways required to maintain kidney
microvascular stability88–90
• Renal biopsy demonstrates chronic thrombotic
microangiopathy, often with foot process effacement88
• DGKE is highly expressed in the brain91 and studies in mice
with a targeted deletion of DGKE suggest a role in
modulating neuronal signalling pathways92–94
Clinical presentation
• Patients with DGKE-mediated HUS present with a few unique
features that can offer clinical clues as to the underlying cause
• Typically presents within the first 12 months of life, with an
estimated 25% of atypical HUS cases in this age group due to
DGKE mutations; the fractional contribution increases to 50%
if there is a positive history of familial disease88
• Nephrotic syndrome is also common within 3–5 years of
diagnosis, a noteworthy clinical finding because heavy
proteinuria is not typically seen with complement-mediated
HUS
• Brocklebank and colleagues reported a high incidence
(6 of 14 individuals) of developmental disorders in their
organ transplantation. HSCT-TMA is a severe compli­
cation of both allogeneic and autologous tran­splantation.
Patients typically present 35–47 days following HSCT with
the classic triad of HUS. Their pathophysiology, clinical
features and management are discussed in panel 3 and
the appendix (pp 10, 22).
Secondary HUS
Secondary HUS refers to any disorder presenting
with HUS features and includes entities such as malig­
nant hypertension140 or autoimmune disorders such as
systemic lupus erythematosus, antiphospholipid anti­
body syndrome, or scleroderma. Whether these disorders
cause HUS or have features that overlap with HUS is not
entirely clear. In malignant hypertension, HUS features
may be secondary to hypertension; control of blood
pressure alone without anti-complement therapy might
be sufficient to treat this disorder. However, complement-
mediated HUS itself can present as a hypertensive
emergency, confusing the diagnosis.141 HUS pathogenesis
1728
cohort, including developmental delay, learning difficulties,
and autistic spectrum disorder87
Management87,88,95
• Supportive management
• Brocklebank and colleagues87 described their experience in
15 patients with numerous relapses while on eculizumab
• Renal half-life is approximately 20 years and those who
progress to end-stage renal disease should undergo kidney
transplantation without the need for eculizumab and no
relapses reported in the transplant
WT1 mutation-associated HUS96–100
• The WT1 gene encodes proteins that regulate progenitor
cells and their differentiation, especially those of the gonads,
uteri, and kidneys
• WT1 variant is pathogenic for Denys–Drash syndrome, a rare
disorder characterised by early-onset nephrotic syndrome
and renal failure, pseudo-hermaphroditism, and a high risk
of Wilms’ tumour
• Pathogenesis of aHUS in WT1 mutation is not fully
understood but several reports suggest podocyte
dysfunction leading to decreased VEGF, contributing to the
development of renal thrombotic microangiopathy
• There are reports of five cases of Denys–Drash syndrome
presenting with atypical HUS; all cases progressed to end-
stage renal disease despite treatment with plasma exchange,
eculizumab, or both, which led to testing for other gene
mutations by whole-exome sequencing and diagnosis of
WT1 mutation; all received renal transplantation without
recurrence of atypical HUS
HUS=haemolytic uraemic syndrome.
in the setting of autoimmune disease is multifactorial.55,142–145
It is important to rule out thrombotic thrombocytopenia
purpura in patients with systemic lupus erythema­
tosus because these entities can sometimes occur
together146,147 Treatment of secondary HUS in the setting
of autoimmunity might include anti-complement
medications, treatment of underlying conditions, or
both.55,144,148–150
Malignancy-induced HUS
Malignancy can induce HUS through a wide variety of
mechanisms, including systemic microvascular meta­
stases, extensive bone marrow invasion, or secondary
necrosis.151 Increased thrombin generation can directly
activate the complement system through C5 cleavage.72,152
HUS syndromes have been reported with metastatic
gastric and ovarian cancers, leukaemias, and lymph­
omas.153–157 Furthermore, many chemotherapeutic drugs
have been associated with HUS (see the section on
drug-induced HUS later). Treatment of the underlying
www.thelancet.com Vol 400 November 12, 2022

Panel 2: Clinical characteristics of patients with HUS associated with disorder of cobalamin metabolism
Epidemiology103,104
• Cobalamin C (cblC) disease, an inborn error of vitamin B12
metabolism, is the most common disorder of cobalamin
metabolism
• Inherited as an autosomal recessive disorder, cblC disease is
caused by mutations in MMACHC and cobalamin G (cblG)
disease is due to methionine synthase deficiency caused by
a mutation in MTR
• cblC disease accounts for fewer than 0·5% of cases of
secondary HUS
• cblG disease also presents with thrombotic
microangiopathy (8 cases reported ever)
• Inherited disorders of cobalamin metabolism should be
considered in infants younger than 1 year of age presenting
with thrombotic microangiopathy because targeted
disease-specific therapy can be life-saving
Pathophysiology
• Suggested mechanism of HUS (appendix p 19) is
endothelial damage induced by hyperhomocysteinaemia,
impaired nitric oxide-dependent inhibition of platelet
aggregation, or induction of a procoagulant state of
endothelium leading to microthrombi formation. Only a
minority of patients with cblC and cblG disease develop
HUS, suggesting that other modifiers have a role
• The hallmarks are hyperhomocysteinaemia with low
methionine in both cblC and cblG; high levels of
methylmalonic acid (MMA) are found in cblC and low MMA in
cblG disease
• Renal biopsy (not necessary for diagnosis) shows
vacuolated appearance of the glomerular basement
membrane more frequently in patients with cblC deficiency
than in other thrombotic microangiopathy controls
(in 6 of 7 patients with cblC deficiency vs 1 of 14 thrombotic
microangiopathy controls; p<0·001)105
Clinical presentation and diagnosis
• cblC and cblG disease most commonly present in early
infancy (within the first few months of life); cblC disease
can manifest at any age
cancer often results in resolution of HUS, but HUS can
recur with relapse of the malignancy.158
Pregnancy-associated aHUS
Pregnancy-associated aHUS refers to TMA resulting from
uncontrolled complement activation during pregnancy or
post partum. It accounts for 7% of total aHUS cases and
up to 20% of all cases of aHUS in women.3,159,160 aHUS
should be suspected when, despite delivery, TMA fails to
improve and extends beyond 72 h, which is the expected
time for recovery in other causes of pregnancy-associated
TMA, including eclampsia, pre-eclampsia, and HELLP
(haemolysis, elevated liver enzymes, low platelet count)
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Seminar
• Clinical features common to both cblC and cblG include
feeding difficulties, failure to thrive, movement disorder,
abnormal muscle tone, developmental delay, megaloblastic
anaemia, neutropenia, venous thrombosis, and embolism.
Additionally, children with cblC disease might be small for
gestational age and have cardiomyopathy and stroke106,107
• When disease onset is in later childhood and adulthood, the
presentation is dominated by neurological manifestations
such as ataxia, cognitive impairment, and psychosis108,109
• Inherited disorders of cobalamin metabolism should be
considered in infants presenting with HUS, especially those
with a history of megaloblastic anaemia and any other
clinical features listed above
• Normal vitamin B12 levels should not preclude further
testing for cobalamin defect
• Screening laboratory tests include: plasma homocysteine
levels, and plasma MMA and plasma amino acid
(methionine levels), which are required to diagnose a
disorder of intracellular cobalamin metabolism
• Confirm diagnosis by genetic testing: MTR mutation in cblG
and MMACHC mutation (>90 different pathogenic variants
have been identified) in cblC110
Management103,110–113
• Stabilise patients in consultation with metabolic specialist
to treat acidosis, reversing catabolism and initiating
parenteral hydroxycobalamin
• Goal of treatment is to lower plasma homocysteine,
maintain plasma methionine in the normal range, and
lower MMA if elevated (cblC)
• Hydroxycobalamin intramuscular form of vitamin B12
supplements the precursor of cobalamin metabolism
• Betaine acts as a methyl donor and helps in the conversion of
homocysteine to methionine
• Folic acid (or folinic acid/leucovorin which efficiently crosses
the blood–brain barrier) replenishes the folate cycle, and
improves plasma levels of homocysteine and methionine
HUS=haemolytic uraemic syndrome. MMACHC=methylmalonic aciduria and homocystinu-
ria, cobalamin type C. MTR=methionine synthase.
syndrome.161,162 The ratio of soluble fms-like tyrosine
kinase-1 (sFlt-1) to placental growth factor is being
increasingly used to exclude pre-eclampsia or eclampsia
and HELLP syndrome, and enables clinicians to search
for other TMA causes, including pregnancy-associated
aHUS.162,163 In women with pregnancy-associated aHUS,
complement abnor­ malities including mutations in
CFH (30%) and CFI (9%) have been demonstrated.164 In
the pre-eculizumab era, a high proportion of cases of
pregnancy-associated aHUS (around 76%) progressed to
end-stage renal disease,159 but eculizumab has been shown
to improve kidney outcomes.164 The optimal duration of
eculizumab therapy is debatable; some experts propose its
1729
 Seminar

Suspected HUS
Haemoglobin <10 g/dL, schistocytes ≥2%, lactate dehydrogenase >450 IU/L,
platelets <150 000/µL, acute kidney injury

Plasma exchange, Thrombotic Shiga toxin-producing STEC-HUS

immunosuppression thrombocytopenic purpura enterohemorrhagic Escherichia Supportive management
ADAMTS13 activity and coli (STEC)
ADAM- ADAMTS13 autoantibodies Stool or rectal swab culture, Shiga
TS13 Shiga toxin PCR or serology toxin-
activity positive
<10%
Parenteral hydroxocobalamine, Metabolism-associated HUS Streptococcus pneumoniae HUS Streptococcus pneumoniae-
oral folinic acid, and betaine Cobalamin C and cobalamin G Blood culture, chest x-ray, lumbar HUS
disease, homocystinaemia, low puncture, Coombs test, Cephalosporin and
methionine, high or low T-antigen testing vancomycin, washed red
methylmalonic acid blood cells, and supportive
Genetics: MMACHC and MTR management

Secondary HUS Infection-associated HUS

Systemic lupus erythematosus, Evaluate if clinically indicated
antiphospholipid syndrome,
malignant hypertension, drugs,
malignancy, transplant

Atypical HUS

C3, C4, factor H, factor I, CD46,

anti-factor H antibody
Genetics: CFH, CFI, CD46, THMD, C3,
CFB
MPLA: CFHR1-5, CFHR1/CFH

Supportive management. DGKE-HUS and WT1-HUS

No reported benefit of Early onset (<2 years of age).
eculizumab or plasma Whole-exome sequencing if not
already included in the genetic
panel

First-line eculizumab within 24 h of onset; if not available, start plasma exchange

with fresh frozen plasma or plasma infusion if plasma exchange not available

Anti-FH antibodies positive if >150 antibody units per mL or >1000 units/mL. Add
plasma exchange and immunosuppression if already started on eculizumab

Figure 3: Suggested diagnostic pathway and treatment for suspected HUS

HUS=haemolytic uraemic syndrome.

discontin­
uation after normalising haematological and
kidney manifestations with monitoring for recurrence in
subsequent pregnancies.165
Drug-induced HUS
Drug-induced TMA occurs due to immune-mediated or
direct toxic effects of medications on the endothe­lium.166,167
TMA resulting from inhibitors of VEGF (anti-
VEGF) involves injury to renal podocytes.168 Quinine-
associated TMA develops secondary to quinine-dependent
anti­
bodies against endothelial cells, platelets, and
leuk­o­cytes.169 Other examples include calcineurin in­hi­bi­
tors (cyclosporin and tacrolimus), mTOR inhibitors
(sirolimus and everolimus), vincristine, gemcita­­bine, and
oxalipla­tin.170,171 As opposed to anti-VEGF and quinine, the
causes of TMA with these agents are diverse and might be
dose-related. Drug-induced TMA should be suspected
when there is a sudden onset of acute kidney injury with
anuria that occurs within days of starting a new
medication, although it can also be delayed. Management
involves stopping the causative medication, although that
alone might not be sufficient, and in patients with
worsening acute kidney injury, other therapies such as
plasma exchange and eculizumab should be considered.
Im­prove­ment of TMA is likely, although some degree of
kidney injury can persist.55
Diagnosis of HUS
Early diagnosis is important because HUS is associated
with acute morbidity and mortality, and delays in

1730 www.thelancet.com Vol 400 November 12, 2022


Panel 3: Main clinical characteristics in patients with transplant-related HUS
Epidemiology114–120
• Thrombotic microangiopathy (TMA) occurring after
haematopoietic stem cell transplantation (HSCT) or solid
organ transplantation (SOT).
• HSCT-TMA: follows allogeneic or autologous
transplantation with an incidence of 3–75% and a mortality
rate of 15–90%.
• SOT-TMA: follows renal, liver, cardiac, lung, or intestinal
transplantation, with an incidence of 0–33% and a mortality
rate of 25–60%.
Pathophysiology121–123
• Caused by systemic or local vascular endothelial injury
triggered by the transplantation process.
• Mechanisms of endothelial injury in HSCT-TMA:
microthrombi formation due to activation of endothelial
cells to produce a pro-coagulant state, antigen-presenting
cells and lymphocytes, and complement.
• The so-called three hit hypothesis proposes that TMA
develops after three insults: 1) underlying predisposition to
endothelial injury; 2) pre-transplant conditioning regimen;
and 3) post-transplant factors causing persistent
endothelial injury.
• The appendix (p 10) lists the risk factors for HSCT-TMA and
biomarkers of endothelial injury.
• Mechanisms of endothelial injury in SOT-TMA:
transplantation surgery, immunosuppressive drugs
(calcineurin inhibitors and mTOR inhibitors), acute
rejection, infection, or relative deficiency of ADAMTS13.
Clinical presentation and diagnosis116,124–133
HSCT-TMA
• Classic triad of renal dysfunction (severe), microangiopathic
haemolytic anaemia, and thrombocytopenia.
• Hypertension an early finding, proteinuria often present.
• Schistocytes on peripheral blood smear is pathognomonic,
but might be absent.
diagnosis can lead to chronic multisystem morbidity. All
types of HUS have similar presentation with some or all
features of the triad of non-immune microangio­pathic
haemolytic anaemia (haemoglobin <10 g/dL) and
fragmented red cells on peripheral smear (schistocytes
≥2%) with either increased lactate dehydrogenase or
undetectable haptoglobin, throm­bocytopenia, and acute
kidney injury. A direct Coombs test is an important
diagnostic step in differentiating HUS from other causes
of immune-mediated haemolysis. A systematic approach
is necessary to evaluate all patients with suspected TMA,
with exclusion of systemic sepsis with or without
consumptive coagulopathy (prolonged prothrombin
time and partial thromboplastin time, low fibrinogen,
elevated D-dimer, and thrombocytopenia). In tropical
countries, infections such as malaria, dengue fever,
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Seminar
• Heart, lungs, brain, and intestines can be affected.
• Diagnosis: tissue histology is gold standard, but often
prohibitive. Diagnostic algorithms available combine clinical
and laboratory markers in lieu of tissue diagnosis.
SOT-TMA
• Thrombocytopenia and Coombs-negative haemolytic
anaemia.
• Microangiopathy, including schistocytes on smear, elevated
lactace dehydrogenase, and low haptoglobin often
observed.
• Microvascular thrombosis can manifest systemically or be
restricted to the kidneys or the graft itself.
See the appendix (p 10) for differential diagnosis of transplant-
related HUS.
Management124–139
HSCT-TMA
• Address underlying or inciting factors and optimise anti-
hypertensive management.
• Plasmapheresis or eculizumab (neither is optimally
effective).
• Other experimental therapies: conversin (C5 inhibitor),
narsoplimab (MASP-2 inhibitor), rituximab, recombinant
thrombomodulin, defibrotide, and daclizumab (anti-CD25).
SOT-TMA
• Trial alternative immunosuppression, implement supportive
measures.
• Plasmapheresis or eculizumab (neither is optimally
effective).
• Basiliximab (anti-CD25) is a potential experimental therapy.
ADAMTS13=a disintegrin and metalloproteinase with thrombospondin type 1 motifs,
member 13. HUS=haemolytic uraemic syndrome.
typhus, and leptospirosis also need to be excluded.
Patients with thrombotic thrombocytopenia purpura
also show features of TMA and can be diagnosed by
testing for ADAMTS13 activity. Once the afore­mentioned
causes of TMA have been excluded, the diagnosis of
HUS is made. Clinical and family history, age at
presentation, recent illnesses and associated symptoms
guide subsequent evaluation. aHUS, especially
complement-mediated HUS, is a diagnosis of exclusion
at presentation and therefore all potential causes of HUS
must be considered when evaluating a patient in the
acute setting.
Several diagnostic algorithms exist that use stepwise
approaches to identify the cause of HUS. A suggested
diagnostic approach for a patient with suspected HUS is
shown in figure 3 (see appendix p 13 for details).
1731
 Seminar
Management of HUS
Supportive care for all types of HUS
Supportive care is similar in all patients with HUS
irrespective of the cause. Increased awareness and early
recognition of symptoms with advanced intensive care
unit availability60,172 and dialysis care have improved
outcomes173 (appendix p 14).
Management of STEC-HUS
Epidemiological data have shown an association between
dehydration and adverse outcomes in patients with STEC
infection.174 Early use of isotonic fluids is recommended
in patients with dysentery, starting from onset of bloody
diarrhoea to the day of onset of HUS and monitoring for
fluid overload in patients with acute kidney injury. The
role of antibiotics, specifically cotrimoxazole and
β-lactams, for STEC gastroenteritis is debated, since these
might induce expression and release of Stx and increase
the risk of HUS.175,176 Tarr and Freedman reinforce the
importance of antibiotic avoidance in possible or definite
STEC infections because of an absence of evidence that
any antibiotic class improves STEC infection versus no
antibiotic treatment, and because of growing evidence
that antibiotics increase the risk of developing HUS when
used to treat early STEC infections.177 Medications that
slow gastric transit, including loperamide, diphenoxylate,
and opioids, should be avoided because they reduce the
colonic excretion of STEC and might be associated with
an increased risk of HUS. The practice of plasma
exchange varies, with no consensus regarding its use.
Although used anecdotally in patients with refractory
illness and severe neurological symptoms, current
evidence does not support plasma exchange or immuno­
adsorption.178 Eculizumab, a humanised monoclonal
anti-C5 antibody that blocks the terminal complement
pathway, has shown remarkable success in aHUS.
However, analysis of the German STEC-HUS registry did
not show a benefit of eculizumab in adults.179 Although
one report did suggest benefit in three children with
neurological involvement,180 the overall evidence of
efficacy and safety of eculizu­ mab in STEC-HUS is
unclear.181 Two placebo-controlled randomised trials have
completed enrolment (ECUSTEC in the UK
[ISRCTN89553116] and ECULISHU in France
[NCT02205541]) to examine the therapeutic role of
eculizumab in STEC-HUS, the results of which should
provide more clear evidence of the utility and safety of its
use in STEC-HUS. Although animal models suggest that
administration of Shiga toxin-binding and neutralising
agents might influence the disease course, clinical studies
have not shown benefit of such drugs. Plasma infusions,
heparin, urokinase, dipyridamole, and glucocorticoids do
not ameliorate the disease course.182
Management of Sp-HUS
Therapy for Sp-HUS remains supportive as discussed
previously. Pneumococcal infection should be treated with
1732
extended-spectrum cephalosporin and vancomycin in
critically ill children with suspected invasive pneu­mococcal
disease. Because of concern that anti-T antigen antibodies
might be present in blood products, dextran washing of
peripheral red blood cells before transfusion is
recommended,45 and plasma-containing blood products
such as fresh frozen plasma are generally avoided.
Successful use of plasmapheresis specifically with albumin
to remove the anti-T antigen anti­ bodies has been
reported;183,184 however, there is little systematic evidence
that it improves outcomes. Because of evidence of
complement activation, there are few reports of eculizumab
use to treat severe cases of Sp-HUS, with improvement
in platelet counts and subjective improvement in neuro-
irritability.47,54 More evidence from controlled trials is
necessary before eculizumab can become standard
therapy.
Improved awareness of Sp-HUS could help to modify
therapy appropriately and improve outcomes. Long-
term follow-up of renal function is indicated to detect
late-onset end-stage renal disease. A sustained
pneumococcal vaccination programme and vigilance for
replacement serotypes will be the key for persistent
reduction in Sp-HUS cases worldwide.
Management of complement-mediated HUS
Complement C5 inhibitors
Eculizumab is a humanised monoclonal IgG antibody
that binds to the C5 complement protein and blocks its
cleavage, thereby preventing the formation of C5b-9,
the membrane attack complex.185 Eculizumab therapy
reduces anaphylatoxin-induced inflammation and limits
the C5b-9 prothrombotic consequences of complement
activation. Three trials, two in adole­scents and adults5,6
and one in paediatric patients7 demon­strated the efficacy
at 26 weeks of weight-based dosing once every 2 weeks
(appendix p 4) for the treatment of aHUS, and long-term
extension data at 2 years confirmed these positive
findings186 (table 2). Eculizumab was approved for the
treatment of aHUS both in the USA and in many
European countries in 2011. Additional eculizumab
efficacy and safety data are now available from nearly a
decade of registry and non-trial patient data.85,187
Ravulizumab, a humanised monoclonal antibody that
blocks terminal complement activation at C5, engineered
from eculizumab, has an extended half-life and can be
administered once every 8 weeks. It is effective in adults
aged 18 years and older with aHUS.188 A paediatric study
(birth to 18 years) also demonstrated safety and efficacy
when administered every 4–8 weeks based on body­
weight189 (appendix p 4) Ravulizumab was approved for
treatment of aHUS in the USA in 2019.
Because dosing of ravulizumab has not been studied
with plasma, use of eculizumab is preferred in the
acute management of aHUS, especially when results
of ADAMTS13 and FH autoantibody levels are
pending. Eculizumab can be safely switched to
www.thelancet.com Vol 400 November 12, 2022
 Seminar

Children: pre-eculizumab era Children: Adults: pre-eculizumab era Adults: eculizumab era trials Adults: Eculizumab post-trial data
(registry data) eculizumab (registry data) ravulizumab (children)
era trials
French Italian Global Trial 3 French Italian Global Trial 1 Trial 2 Trial 4 Trial 5* Turkish registry86† Menne
registry registry registry (n=22)7 registry registry registry (n= 17)6 (n=20) 6 (n=41)5 (n=56)137 et al187 ‡
(n=89)66 (n=149)67 (n=851)84 (n=89)66 (n=149) 67 (n=851)69
First episode 17% ·· 15% ·· 46% ·· 22% ·· ·· ·· ·· ··
6 months ·· ·· ·· 9% ·· ·· ·· 6% 10% 15% 28% ·· ··
1 year 29% ·· 5% 9% 56% ·· 9% 6% 10% 15% ·· ··
2 years ·· ·· ·· ·· ·· ·· ·· 12% 10% ·· ·· All patients: 10% ··
Eculizumab-
treated patients:
5%
3 years ·· 48% 2% ·· ·· 67% 4% ·· ·· ·· ·· ·· ··
5 years 36% ·· 1% ·· 64% 7% ·· ·· ·· ·· ·· 8·1%
*34/47 patients at chronic kidney disease stage 5 and 7/47 at chronic kidney disease stage 4 at baseline and 13/47 (with chronic kidney disease stage 5 at last follow-up. †5 of the eculizumab-treated patients had
low glomerular filtration rate at the start of treatment; glomerular filtration rate at last follow-up (1·7 years) >90 mL/min per 1·73m2 in 69·6% patients (23/33) in the plasma-treated group and 66% (68/103) of
eculizumab-treated patients. ‡Prospective long-term follow-up of trials 1–5.

Table 2: Percentage of patients with atypical haemolytic uraemic syndrome who progressed to end-stage renal disease or died in the pre-eculizumab era, in eculizumab era trials, and
post-trial data

ravulizumab once a patient’s clinical status is stable.
Meningococcal vaccination, prophylaxis, or both are
important before starting complement 5 inhibitors
(appendix p 15).
Frequency and duration of anti-complement therapy
The optimal duration of eculizumab treatment for
aHUS is unknown. High cost, risk of infection, and
unknown long-term sequelae have raised the
question of whether discontinuation of eculizumab is
safe. Additionally, there are reports of hepatotoxicity
with eculizumab.190,191 There are few retrospective series,
mostly in adults, showing eculizumab discontinuation
with close monitoring for relapse is feasible.192–195 In 2021,
a prospective multicentre study in 55 patients
with aHUS (including children and adults) in France
showed that the risk of aHUS relapse after eculizumab
discontinuation (with close monitoring, including urine
dipstick for albuminuria and haematuria twice weekly)
was low when there was no detected complement gene
variant,196 supporting results from other retrospective
studies (appendix pp 5–6).
Based on the effect of eculizumab in patients with
paroxysmal nocturnal haemoglobinuria, trials in
patients with aHUS aimed at reaching trough levels for
eculizumab between 50 and 100 μg/mL, which is the
level considered necessary to block complement (CH50
activity <10%). However, all patients were treated with
fixed doses based on their weight and therapeutic
drug monitoring was not done.194 As a result, serum
eculizumab levels above this target were often reached,
prompting clinical investigators to adapt the treatment
schedule by either increasing the interval or decreasing
the dosage to maintain recommended trough levels, to
maintain complement blockade, or both.197–200 Based on
these reports, extended dose intervals up to 4–6 weeks
or lower doses are feasible options (appendix pp 7–8).
Large multicentre prospective studies including biopsy-
proven remission with varying doses of both
eculizumab and ravulizumab are required to
standardise long-term management of aHUS in
patients with rare variants in complement genes who
are at a high risk of relapse.
Plasma therapy
Plasma therapy, including plasma exchange or plasma
infusions, was the first line of treatment for aHUS in the
pre-eculizumab era based on experience in patients with
thrombotic thrombocytopenia purpura. No prospective
trials have been done, but registry data66–69 have shown
renal outcome is poor in patients with aHUS treated with
plasma therapy (table 2). Although eculizumab has
replaced therapeutic plasma exchange as the first-line
treatment for aHUS in many countries, plasma exchange
continues to be the standard first-line treatment option
for aHUS when eculizumab is inaccessible (see
appendix p 16 for guideline) and for FH autoantibodies-
associated HUS (appendix p 12).201 Plasma exchange
might also have a role in severe cases of STEC-HUS,
potentially decreasing circulating cytokines, Stx toxin,
and unusually large von Willebrand factor multimers that
contribute to endothelial injury, although little data exist
to support its routine use.202
Transplantation
Eculizumab has dramatically improved the outcome of
kidney transplantation in patients with aHUS; however, its
use for all transplant recipients is questioned. To
personalise aHUS management after transplanta­ tion,
Zuber and colleagues retrospectively stratified recurrence
risk as high, moderate, and low, and found that eculizumab
is strongly and independently associated with significantly

www.thelancet.com Vol 400 November 12, 2022 1733

 Seminar
reduced recurrence risk (hazard ratio 0·05, p<0·001) and
longer graft survival in patients in whom complement
genetics and a past medical history predict a high or
moderate risk of post-transplant recurrence.203 This
recommendation has been adopted by Kidney Disease
Improving Global Outcomes204 (appendix p 9). Global
registry analysis also found significantly better early graft
function in patients who received prophylactic eculizumab
treatment compared with those who received eculizumab
post-transplant.205 Treatment duration remains contro­
versial and information about eculizumab withdrawal
after transplantation is scarce. Living related kidney
donation carries an increased risk of de-novo aHUS in the
donor and recurrence in the recipient if the donor carries
an at-risk genetic variant.206 Therefore, potential donors
with evidence of abnormal alternative complement
pathway activity should be excluded. Liver transplant
remains an option in patients with liver-derived comple­
ment protein abnormalities, in particular for renal
transplant recipients with uncontrolled disease activity
despite eculizumab therapy.
Management of HSCT-TMA
At this time, there are no US Food and Drug Administration
(FDA)-approved anti-complement agents for HSCT-TMA,
but they are becoming more commonly used. Various anti-
complement therapies with different mechanisms of
action, including anti-C5 (eculizumab and conversin) and
mannan-binding lectin-associated serine protease-2
inhibition (MASP-2, narsoplimab), have been evaluated as
potential therapies for HSCT-TMA (panel 3).
Eculizumab use in HSCT-TMA is mostly limited to
small retrospective cohorts.207–212 A prospective study on
its use in 64 paediatric patients showed a 64% response
rate and 66% survival at 1 year.213 Eculizumab can be
considered a front-line therapy for HSCT-TMA, with
titration of dosing based on CH50 levels.211–213 Evidence on
the use of ravulizumab for HSCT-TMA is scarce. There is
one case report on the use of conversin in a child with
HSCT-TMA and a mutation in C5 that conferred
resistance to eculizumab,214 although the patient in this
report died from HSCT-TMA.
Narsoplimab is a MASP-2 inhibitor that blocks
the lectin pathway of complement. A study using narso­
plimab in 28 adult patients with HSCT-TMA showed
improvement in organ function in 74% (20/27), with a
median overall survival of 274 days (95% CI 103–not
estimable). The drug was well tolerated with no safety
concerns.215 The FDA has yet to approve narsoplimab for
the treatment of HSCT-TMA, requesting more data after
results from the single-arm, open-label phase 2 trial215
were submitted in mid-2021.
Monitoring response to eculizumab therapy and non-
responders
The first indication of HUS recovery or response to
eculizumab therapy is normalisation of the platelet count,
1734
and more than 80% of dialysis-dependent patients are able
to discontinue dialysis within a median time of
7 days (range 4–15 days). In initial prospective trials, more
than 80% of patients with thrombocytopenia had
normalised platelet counts by a median time of 7 days
(range 1–80 days). The median time for LDH normal­
isation was 48 days (range 1–153 days). If platelet count
normalisation is not observed by week 2, assessment of
adequacy of complement blockade (CH50 activity <10%)
and eculizumab levels (50–100 µg/mL) are important.
Other complement functional assays are being
eval­ua­ted for monitoring of optimal complement blockade
(appendix p 11). When there is a poor haematological and
renal response, one must rule out the presence of a C5
polymorphism impairing binding of eculizumab to C5216
and/or consider non-complement-mediated HUS,
including that caused by DGKE and WT1 mutations.
Emerging therapies
Crovalimab is a subcutaneous long-acting C5 inhibitor
with sequential monoclonal antibody recycling technology
that binds efficiently to C5. Clinical trials are underway
testing its use in pediatric (COMMUTE-p; NCT04958265)
and adult (COMMUTE-a; NCT04861259) patients with
aHUS. As in the case of eculizumab, newer complement
blocking agents are being studied in patients with
paroxysmal nocturnal haemoglobinuria with potential
for use in aHUS. These new agents include pozelimab, a
fully human monoclonal IgG4P antibody directed
against C5 that has been shown to be a safe C5 inhibitor
with subcutaneous dosing in healthy volunteers
(NCT03946748).
Several proximal complement protein inhibitors
targeting C3, factor B, and factor D are being studied in
clinical trials for a variety of complement-mediated
diseases.217 Another novel therapeutic agent that has been
described as a potential option for complement-related
disorders is a synthetic fusion protein, MFHR1, which is
composed of the regulatory components of CFH and
CFHR1. MFHR1 modulates multiple levels of the
alternative complement pathway, including decay of the
C3 convertase and inhibition of the C5 convertase.218,219
When available for clinical use, these agents will be
important additions to the treatment options for
complement-mediated aHUS.
Summary
HUS is a clinical condition comprised of a triad of non-
immune microangiopathic haemolytic anaemia,
throm­bo­cyto­penia, and acute kidney injury. The unifying
feature of this heterogeneous group of diseases is
endothelial damage. Although the classification of HUS is
constantly evolving, one based on aetiology is used
in this Seminar. Disease epidemiology, pathogenesis,
clinical presentation and management are discussed. The
most common type of HUS, especially in children
younger than 5 years, is STEC-HUS, treatment of which is
www.thelancet.com Vol 400 November 12, 2022

supportive. Complement-mediated HUS is extremely rare
and although it once carried very high morbidity and
mortality, treatment with anti-complement therapies has
made end-stage renal disease and death unusual in
high-income countries. Further studies are needed to
determine the optimal frequency and duration of
complement blockers, and guidelines for monitoring
optimal complement blockade would be helpful. There
are many other causes of HUS, including those associated
with mutations in non-complement genes and HUS that
develops in association with a primary disease process.
For many of these rarer presentations of HUS, our
understanding of the underlying patho­ physiology is
incomplete and anti-complement is either not indicated
or its role in treatment remains to be defined. An urgent
need remains to make affordable versions of anti-
complement agents available in low-income countries.
Contributors
All authors contributed equally.
Declaration of interests
MM declares no conflicts of interest related to this topic but has served as
site principal investigator for use of lumasiran for primary hyperoxaluria
type 1 by Alnylam Pharmaceuticals. SES has received research funding
from Alexion Pharmaceuticals to test pre-clinical complement agents in
murine models of complement-mediated disease. RJHS directs the
Molecular Otolaryngology and Renal Research Laboratories
(Iowa City, IA, USA) where genetic and complement testing for atypical
HUS and the TMAs is done. AB declares no competing interests.
Acknowledgments
We thank Geetika Singh (All India Institute of Medical Sciences,
New Delhi, Delhi, India) for providing pathology slides of thrombotic
microangiopathy.
References
1 Loirat C, Frémeaux-Bacchi V. Atypical hemolytic uremic syndrome.
Orphanet J Rare Dis 2011; 6: 60.
2 Nester CM, Barbour T, de Cordoba SR, et al. Atypical aHUS: state of
the art. Mol Immunol 2015; 67: 31–42.
3 Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome.
N Engl J Med 2009; 361: 1676–87.
4 Zheng XL, Vesely SK, Cataland SR, et al. ISTH guidelines for the
diagnosis of thrombotic thrombocytopenic purpura.
J Thromb Haemost 2020; 18: 2486–95.
5 Fakhouri F, Hourmant M, Campistol JM, et al. Terminal
complement inhibitor eculizumab in adult patients with atypical
hemolytic uremic syndrome: a single-arm, open-label trial.
Am J Kidney Dis 2016; 68: 84–93.
6 Legendre CM, Licht C, Muus P, et al. Terminal complement
inhibitor eculizumab in atypical hemolytic-uremic syndrome.
N Engl J Med 2013; 368: 2169–81.
7 Greenbaum LA, Fila M, Ardissino G, et al. Eculizumab is a safe and
effective treatment in pediatric patients with atypical hemolytic
uremic syndrome. Kidney Int 2016; 89: 701–11.
8 Majowicz SE, Scallan E, Jones-Bitton A, et al. Global incidence of
human Shiga toxin-producing Escherichia coli infections and deaths:
a systematic review and knowledge synthesis. Foodborne Pathog Dis
2014; 11: 447–55.
9 Alconcher LF, Balestracci A, Coccia PA, et al. Hemolytic uremic
syndrome associated with Shiga toxin-producing Escherichia coli
infection in Argentina: update of serotypes and genotypes and their
relationship with severity of the disease. Pediatr Nephrol 2021;
36: 2811–17.
10 Tack DM, Kisselburgh HM, Richardson LC, et al. Shiga toxin-
producing Escherichia coli outbreaks in the United States, 2010–2017.
Microorganisms 2021; 9: 1529.
11 Valilis E, Ramsey A, Sidiq S, DuPont HL. Non-O157 Shiga toxin-
producing Escherichia coli–a poorly appreciated enteric pathogen:
systematic review. Int J Infect Dis 2018; 76: 82–87.
www.thelancet.com Vol 400 November 12, 2022
Seminar
12 Vishram B, Jenkins C, Greig DR, et al. The emerging importance of
Shiga toxin-producing Escherichia coli other than serogroup O157 in
England. J Med Microbiol 2021; 70: 001375.
13 Joseph A, Cointe A, Mariani Kurkdjian P, Rafat C, Hertig A.
Shiga toxin-associated hemolytic uremic syndrome: a narrative
review. Toxins 2020; 12: 67.
14 Marshall KE, Hexemer A, Seelman SL, et al. Lessons learned from a
decade of investigations of shiga toxin-producing Escherichia coli
outbreaks linked to leafy greens, United States and Canada.
Emerg Infect Dis 2020; 26: 2319–28.
15 Bielaszewska M, Mellmann A, Zhang W, et al. Characterisation of
the Escherichia coli strain associated with an outbreak of haemolytic
uraemic syndrome in Germany, 2011: a microbiological study.
Lancet Infect Dis 2011; 11: 671–76.
16 Wijnsma KL, Schijvens AM, Rossen JWA, Kooistra-Smid AMDM,
Schreuder MF, van de Kar NCAJ. Unusual severe case of hemolytic
uremic syndrome due to Shiga toxin 2d-producing E. coli O80:H2.
Pediatr Nephrol 2017; 32: 1263–68.
17 Sawyer C, Vishram B, Jenkins C, et al. Epidemiological
investigation of recurrent outbreaks of haemolytic uraemic
syndrome caused by Shiga toxin-producing Escherichia coli serotype
O55:H7 in England, 2014–2018. Epidemiol Infect 2021; 149: e108.
18 Ardissino G, Vignati C, Masia C, et al. Bloody diarrhea and shiga toxin-
producing Escherichia coli hemolytic uremic syndrome in children:
data from the ItalKid-HUS network. J Pediatr 2021; 237: 34–40.e1.
19 Lee MS, Yoon JW, Tesh VL. Editorial: recent advances in
understanding the pathogenesis of shiga toxin-producing Shigella
and Escherichia coli. Front Cell Infect Microbiol 2020; 10: 620703.
20 Menge C. Molecular biology of Escherichia coli Shiga toxins’ effects
on mammalian cells. Toxins 2020; 12: 345.
21 Buelli S, Zoja C, Remuzzi G, Morigi M. Complement activation
contributes to the pathophysiology of Shiga toxin-associated
hemolytic uremic syndrome. Microorganisms 2019; 7: 15.
22 Westra D, Volokhina EB, van der Molen RG, et al. Serological and
genetic complement alterations in infection-induced and
complement-mediated hemolytic uremic syndrome. Pediatr Nephrol
2017; 32: 297–309.
23 Noris M, Mescia F, Remuzzi G. STEC-HUS, atypical HUS and TTP
are all diseases of complement activation. Nat Rev Nephrol 2012;
8: 622–33.
24 Netti GS, Santangelo L, Paulucci L, et al. Low C3 serum levels
predict severe forms of STEC-HUS with neurologic involvement.
Front Med 2020; 7: 357.
25 Obata F, Tohyama K, Bonev AD, et al. Shiga toxin 2 affects the
central nervous system through receptor globotriaosylceramide
localized to neurons. J Infect Dis 2008; 198: 1398–406.
26 Eisenhauer PB, Jacewicz MS, Conn KJ, et al. Escherichia coli Shiga
toxin 1 and TNF-alpha induce cytokine release by human cerebral
microvascular endothelial cells. Microb Pathog 2004; 36: 189–96.
27 Pifer R, Sperandio V. The interplay between the microbiota and
enterohemorrhagic Escherichia coli. Microbiol Spectr 2014; 2: doi:
10.1128/microbiolspec.EHEC-0015-2013.
28 Travert B, Dossier A, Jamme M, et al. Shiga toxin-associated
hemolytic uremic syndrome in adults, France, 2009–2017.
Emerg Infect Dis 2021; 27: 1876–85.
29 Travert B, Rafat C, Mariani P, et al. Shiga toxin-associated hemolytic
uremic syndrome: specificities of adult patients and implications
for critical care management. Toxins 2021; 13: 306.
30 Costigan C, Raftery T, Carroll AG, et al. Neurological involvement in
children with hemolytic uremic syndrome. Eur J Pediatr 2022;
181: 501–12.
31 Nathanson S, Kwon T, Elmaleh M, et al. Acute neurological
involvement in diarrhea-associated hemolytic uremic syndrome.
Clin J Am Soc Nephrol 2010; 5: 1218–28.
32 Khalid M, Andreoli S. Extrarenal manifestations of the hemolytic
uremic syndrome associated with Shiga toxin-producing Escherichia
coli (STEC HUS). Pediatr Nephrol 2019; 34: 2495–507.
33 Brown CC, Garcia X, Bhakta RT, Sanders E, Prodhan P. Severe
acute neurologic involvement in children with hemolytic-uremic
syndrome. Pediatrics 2021; 147: e2020013631.
34 Andreoli S, Bergstein J. Exocrine and endocrine pancreatic
insufficiency and calcinosis after hemolytic uremic syndrome.
J Pediatr 1987; 110: 816–17.
1735
 Seminar
35 Suri RS, Clark WF, Barrowman N, et al. Diabetes during diarrhea-
associated hemolytic uremic syndrome: a systematic review and
meta-analysis. Diabetes Care 2005; 28: 2556–62.
36 Gallo EG, Gianantonio CA. Extrarenal involvement in
diarrhoea-associated haemolytic-uraemic syndrome. Pediatr Nephrol
1995; 9: 117–19.
37 Constantinescu AR, Bitzan M, Weiss LS, et al. Non-enteropathic
hemolytic uremic syndrome: causes and short-term course.
Am J Kidney Dis 2004; 43: 976–82.
38 Mizusawa Y, Pitcher LA, Burke JR, Falk MC, Mizushima W. Survey
of haemolytic-uraemic syndrome in Queensland 1979–1995.
Med J Aust 1996; 165: 188–91.
39 Copelovitch L, Kaplan BS. Streptococcus pneumoniae-associated
hemolytic uremic syndrome. Pediatr Nephrol 2008; 23: 1951–56.
40 Cabrera GR, Fortenberry JD, Warshaw BL, Chambliss CR,
Butler JC, Cooperstone BG. Hemolytic uremic syndrome associated
with invasive Streptococcus pneumoniae infection. Pediatrics 1998;
101: 699–703.
41 Copelovitch L, Kaplan BS. Streptococcus pneumoniae-associated
hemolytic uremic syndrome: classification and the emergence of
serotype 19A. Pediatrics 2010; 125: e174–82.
42 Loupiac A, Elayan A, Cailliez M, et al. Diagnosis of Streptococcus
pneumoniae-associated hemolytic uremic syndrome.
Pediatr Infect Dis J 2013; 32: 1045–49.
43 Makwana A, Sheppard C, Fry NK, Ladhani SN. Pneumococcal-
related hemolytic uremic syndrome in the United Kingdom: national
surveillance, 2006–2016. Pediatr Infect Dis J 2019; 38: e254–59.
44 Klein PJ, Bulla M, Newman RA, et al. Thomsen-Friedenreich
antigen in haemolytic-uraemic syndrome. Lancet 1977; 2: 1024–25.
45 Crookston KP, Reiner AP, Cooper LJ, Sacher RA, Blajchman MA,
Heddle NM. RBC T activation and hemolysis: implications for
pediatric transfusion management. Transfusion 2000; 40: 801–12.
46 Gilbert RD, Nagra A, Haq MR. Does dysregulated complement
activation contribute to haemolytic uraemic syndrome secondary to
Streptococcus pneumoniae? Med Hypotheses 2013; 81: 400–03.
47 Szilágyi A, Kiss N, Bereczki C, et al. The role of complement in
Streptococcus pneumoniae-associated haemolytic uraemic syndrome.
Nephrol Dial Transplant 2013; 28: 2237–45.
48 Spinale JM, Ruebner RL, Kaplan BS, Copelovitch L. Update on
Streptococcus pneumoniae associated hemolytic uremic syndrome.
Curr Opin Pediatr 2013; 25: 203–08.
49 Gómez Delgado I, Corvillo F, Nozal P, et al. Complement genetic
variants and FH desialylation in S. pneumoniae-haemolytic uraemic
syndrome. Front Immunol 2021; 12: 641656.
50 Ariceta G, Besbas N, Johnson S, et al. Guideline for the
investigation and initial therapy of diarrhea-negative hemolytic
uremic syndrome. Pediatr Nephrol 2009; 24: 687–96.
51 Brandt J, Wong C, Mihm S, et al. Invasive pneumococcal disease
and hemolytic uremic syndrome. Pediatrics 2002; 110: 371–76.
52 Huang DT, Chi H, Lee HC, Chiu NC, Huang FY. T-antigen
activation for prediction of pneumococcus-induced hemolytic
uremic syndrome and hemolytic anemia. Pediatr Infect Dis J 2006;
25: 608–10.
53 Waters AM, Kerecuk L, Luk D, et al. Hemolytic uremic syndrome
associated with invasive pneumococcal disease: the United
Kingdom experience. J Pediatr 2007; 151: 140–44.
54 Banerjee R, Hersh AL, Newland J, et al. Streptococcus pneumoniae-
associated hemolytic uremic syndrome among children in North
America. Pediatr Infect Dis J 2011; 30: 736–39.
55 Palma LMP, Sridharan M, Sethi S. Complement in secondary
thrombotic microangiopathy. Kidney Int Rep 2021; 6: 11–23.
56 Noris M, Benigni A, Remuzzi G. The case of complement
activation in COVID-19 multiorgan impact. Kidney Int 2020;
98: 314–22.
57 Zipfel PF, Mache C, Müller D, et al. DEAP-HUS: deficiency of
CFHR plasma proteins and autoantibody-positive form of hemolytic
uremic syndrome. Pediatr Nephrol 2010; 25: 2009–19.
58 Franchini M. Atypical hemolytic uremic syndrome: from diagnosis
to treatment. Clin Chem Lab Med 2015; 53: 1679–88.
59 Noris M, Bucchioni S, Galbusera M, et al. Complement factor
H mutation in familial thrombotic thrombocytopenic purpura with
ADAMTS13 deficiency and renal involvement. J Am Soc Nephrol
2005; 16: 1177–83.
1736
60 Campistol JM, Arias M, Ariceta G, et al. An update for atypical
haemolytic uraemic syndrome: diagnosis and treatment.
A consensus document. Nefrologia 2015; 35: 421–47.
61 Thompson RA, Winterborn MH. Hypocomplementaemia due
to a genetic deficiency of beta 1H globulin. Clin Exp Immunol 1981;
46: 110–9.
62 Warwicker P, Goodship TH, Donne RL, et al. Genetic studies into
inherited and sporadic hemolytic uremic syndrome. Kidney Int
1998; 53: 836–44.
63 George JN, Nester CM. Syndromes of thrombotic microangiopathy.
N Engl J Med 2014; 371: 1847–48.
64 Thurman JM, Holers VM. The central role of the alternative
complement pathway in human disease. J Immunol 2006;
176: 1305–10.
65 Ricklin D. Manipulating the mediator: modulation of the alternative
complement pathway C3 convertase in health, disease and therapy.
Immunobiology 2012; 217: 1057–66.
66 Fremeaux-Bacchi V, Fakhouri F, Garnier A, et al. Genetics and
outcome of atypical hemolytic uremic syndrome: a nationwide
French series comparing children and adults. Clin J Am Soc Nephrol
2013; 8: 554–62.
67 Noris M, Caprioli J, Bresin E, et al. Relative role of genetic
complement abnormalities in sporadic and familial aHUS and their
impact on clinical phenotype. Clin J Am Soc Nephrol 2010; 5: 1844–59.
68 Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ. Mutations
in alternative pathway complement proteins in American patients
with atypical hemolytic uremic syndrome. Hum Mutat 2010;
31: E1445–60.
69 Schaefer F, Ardissino G, Ariceta G, et al. Clinical and genetic
predictors of atypical hemolytic uremic syndrome phenotype and
outcome. Kidney Int 2018; 94: 408–18.
70 Bresin E, Rurali E, Caprioli J, et al. Combined complement gene
mutations in atypical hemolytic uremic syndrome influence clinical
phenotype. J Am Soc Nephrol 2013; 24: 475–86.
71 Valoti E, Alberti M, Tortajada A, et al. A novel atypical hemolytic
uremic syndrome-associated hybrid CFHR1/CFH gene encoding
a fusion protein that antagonizes factor H-dependent complement
regulation. J Am Soc Nephrol 2015; 26: 209–19.
72 Krisinger MJ, Goebeler V, Lu Z, et al. Thrombin generates
previously unidentified C5 products that support the terminal
complement activation pathway. Blood 2012; 120: 1717–25.
73 Ferreira VP, Pangburn MK, Cortés C. Complement control protein
factor H: the good, the bad, and the inadequate. Mol Immunol 2010;
47: 2187–97.
74 Eyler SJ, Meyer NC, Zhang Y, Xiao X, Nester CM, Smith RJ. A novel
hybrid CFHR1/CFH gene causes atypical hemolytic uremic
syndrome. Pediatr Nephrol 2013; 28: 2221–25.
75 Caprioli J, Noris M, Brioschi S, et al. Genetics of HUS: the impact
of MCP, CFH, and IF mutations on clinical presentation, response
to treatment, and outcome. Blood 2006; 108: 1267–79.
76 Delvaeye M, Noris M, De Vriese A, et al. Thrombomodulin
mutations in atypical hemolytic-uremic syndrome. N Engl J Med
2009; 361: 345–57.
77 Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, et al.
Differential impact of complement mutations on clinical
characteristics in atypical hemolytic uremic syndrome.
J Am Soc Nephrol 2007; 18: 2392–400.
78 El Karoui K, Boudhabhay I, Petitprez F, et al. Impact of
hypertensive emergency and rare complement variants on the
presentation and outcome of atypical hemolytic uremic syndrome.
Haematologica 2019; 104: 2501–11.
79 Fidan K, Göknar N, Gülhan B, et al. Extra-renal manifestations of
atypical hemolytic uremic syndrome in children. Pediatr Nephrol
2018; 33: 1395–403.
80 Formeck C, Swiatecka-Urban A. Extra-renal manifestations of atypical
hemolytic uremic syndrome. Pediatr Nephrol 2019; 34: 1337–48.
81 Johnson S, Stojanovic J, Ariceta G, et al. An audit analysis of a
guideline for the investigation and initial therapy of diarrhea
negative (atypical) hemolytic uremic syndrome. Pediatr Nephrol
2014; 29: 1967–78.
82 Vilalta R, Lara E, Madrid A, Chocron S, Muñoz M, Casquero A,
Nieto J. Long-term eculizumab improves clinical outcomes in atypical
hemolytic uremic syndrome. Pediatr Nephrol 2012; 27: 2323–26.
www.thelancet.com Vol 400 November 12, 2022

83 Kaplan BS, Garcia CD, Chesney RW, Segar WE, Giugno K, Chem R.
Peripheral gangrene complicating idiopathic and recessive
hemolytic uremic syndromes. Pediatr Nephrol 2000; 14: 985–89.
84 Ozel A, Calişkan U, Gücer S. Peripheral gangrene complicating
hemolytic uremic syndrome in a child. Pediatr Nephrol 2003;
18: 465–67.
85 Ardissino G, Tel F, Testa S, et al. Skin involvement in atypical
hemolytic uremic syndrome. Am J Kidney Dis 2014; 63: 652–55.
86 Besbas N, Gulhan B, Soylemezoglu O, et al. Turkish pediatric
atypical hemolytic uremic syndrome registry: initial analysis of
146 patients. BMC Nephrol 2017; 18: 6.
87 Brocklebank V, Kumar G, Howie AJ, et al. Long-term outcomes and
response to treatment in diacylglycerol kinase epsilon nephropathy.
Kidney Int 2020; 97: 1260–74.
88 Lemaire M, Frémeaux-Bacchi V, Schaefer F, et al. Recessive
mutations in DGKE cause atypical hemolytic-uremic syndrome.
Nat Genet 2013; 45: 531–36.
89 Ozaltin F, Li B, Rauhauser A, et al. DGKE variants cause a
glomerular microangiopathy that mimics membranoproliferative
GN. J Am Soc Nephrol 2013; 24: 377–84.
90 Liu D, Ding Q, Dai DF, et al. Loss of diacylglycerol kinase ε causes
thrombotic microangiopathy by impairing endothelial VEGFA
signaling. JCI Insight 2021; 6: e146959.
91 Shulga YV, Topham MK, Epand RM. Regulation and functions of
diacylglycerol kinases. Chem Rev 2011; 111: 6186–208.
92 Tang W, Bunting M, Zimmerman GA, McIntyre TM, Prescott SM.
Molecular cloning of a novel human diacylglycerol kinase highly
selective for arachidonate-containing substrates. J Biol Chem 1996;
271: 10237–41.
93 Rodriguez de Turco EB, Tang W, Topham MK, et al. Diacylglycerol
kinase epsilon regulates seizure susceptibility and long-term
potentiation through arachidonoyl-inositol lipid signaling.
Proc Natl Acad Sci USA 2001; 98: 4740–45.
94 Milne SB, Ivanova PT, Armstrong MD, et al. Dramatic differences
in the roles in lipid metabolism of two isoforms of diacylglycerol
kinase. Biochemistry 2008; 47: 9372–79.
95 Sánchez Chinchilla D, Pinto S, Hoppe B, et al. Complement
mutations in diacylglycerol kinase-ε-associated atypical hemolytic
uremic syndrome. Clin J Am Soc Nephrol 2014; 9: 1611–19.
96 Denys P Malvaux P, Van Den Berghe H, Tanghe W, Proesmans W.
Association of an anatomo-pathological syndrome of male
pseudohermaphroditism, Wilms’ tumor, parenchymatous
nephropathyand XX/XY mosaicism. Arch Fr Pediatr 1967;
24: 729–39.
97 Manivel JC, Sibley RK, Dehner LP. Complete and incomplete
Drash syndrome: a clinicopathologic study of five cases of a
dysontogenetic-neoplastic complex. Hum Pathol 1987; 18: 80–89.
98 Sherbotie JR, van Heyningen V, Axton R, Williamson K, Finn LS,
Kaplan BS. Hemolytic uremic syndrome associated with Denys-
Drash syndrome. Pediatr Nephrol 2000; 14: 1092–97.
99 Alge JL, Wenderfer SE, Hicks J, et al. Hemolytic uremic syndrome
as the presenting manifestation of WT1 mutation and Denys-Drash
syndrome: a case report. BMC Nephrol 2017; 18: 243.
100 Cheng C, Chen L, Wen S, Lin Z, Jiang X. Case report: Denys–
Drash syndrome with WT1 causative variant presenting as
atypical hemolytic uremic syndrome. Front Pediatr 2020;
8: 605889.
101 Walsh PR, Johnson S, Brocklebank V, Salvatore J, Christian M,
Kavanagh D. Glucose-6-phosphate dehydrogenase deficiency
mimicking atypical hemolytic uremic syndrome. Am J Kidney Dis
2018; 71: 287–90.
102 Luzzatto L, Ally M, Notaro R. Glucose-6-phosphate dehydrogenase
deficiency. Blood 2020; 136: 1225–40.
103 Mullikin D, Pillai N, Sanchez R, et al. Megaloblastic anemia
progressing to severe thrombotic microangiopathy in patients with
disordered vitamin B. J Pediatr 2018; 202: 315–19.e2.
104 Bayer G, von Tokarski F, Thoreau B, et al. Etiology and outcomes of
thrombotic microangiopathies. Clin J Am Soc Nephrol 2019;
14: 557–66.
105 Lemoine M, François A, Grangé S, et al. Cobalamin C deficiency
induces a typical histopathological pattern of renal arteriolar and
glomerular thrombotic microangiopathy. Kidney Int Rep 2018;
3: 1153–62.
www.thelancet.com Vol 400 November 12, 2022
Seminar
106 Rosenblatt DS, Aspler AL, Shevell MI, Pletcher BA, Fenton WA,
Seashore MR. Clinical heterogeneity and prognosis in combined
methylmalonic aciduria and homocystinuria (cblC).
J Inherit Metab Dis 1997; 20: 528–38.
107 Lerner-Ellis JP, Anastasio N, Liu J, et al. Spectrum of mutations in
MMACHC, allelic expression, and evidence for genotype-phenotype
correlations. Hum Mutat 2009; 30: 1072–81.
108 Tsai AC, Morel CF, Scharer G, et al. Late-onset combined
homocystinuria and methylmalonic aciduria (cblC) and
neuropsychiatric disturbance. Am J Med Genet A 2007;
143A: 2430–34.
109 Thauvin-Robinet C, Roze E, Couvreur G, et al. The adolescent
and adult form of cobalamin C disease: clinical and molecular
spectrum. J Neurol Neurosurg Psychiatry 2008; 79: 725–28.
110 Sloan JL, Carrillo N, Adams D, Venditti CP. Disorders of
intracellular cobalamin metabolism. In: Adam MP, Mirzaa GM,
Pagon RA, et al, eds. GeneReviews® [Internet]. Seattle, WA:
University of Washington, 2018.
111 Craig SA. Betaine in human nutrition. Am J Clin Nutr 2004;
80: 539–49.
112 Vidal-Alaball J, Butler CC, Cannings-John R, et al. Oral vitamin B12
versus intramuscular vitamin B12 for vitamin B12 deficiency.
Cochrane Database Syst Rev 2005; 3: CD004655.
113 Ardissino G, Perrone M, Tel F, et al. Late onset cobalamin disorder
and hemolytic uremic syndrome: a rare cause of nephrotic
syndrome. Case Rep Pediatr 2017; 2017: 2794060.
114 Ponticelli C, Banfi G. Thrombotic microangiopathy after kidney
transplantation. Transpl Int 2006; 19: 789–94.
115 Jodele S, Davies SM, Lane A, et al. Diagnostic and risk criteria for
HSCT-associated thrombotic microangiopathy: a study in children
and young adults. Blood 2014; 124: 645–53.
116 Gavriilaki E, Sakellari I, Batsis I, et al. Transplant-associated
thrombotic microangiopathy: incidence, prognostic factors,
morbidity, and mortality in allogeneic hematopoietic cell
transplantation. Clin Transplant 2018; 32: e13371.
117 Schoettler M, Lehmann L, Li A, Ma C, Duncan C. Thrombotic
microangiopathy following pediatric autologous hematopoietic cell
transplantation: a report of significant end-organ dysfunction in
eculizumab-treated survivors. Biol Blood Marrow Transplant 2019;
25: e163–68.
118 Tolbert VP, Dvorak CC, Golden C, et al. Risk factors for transplant-
associated thrombotic microangiopathy after autologous
hematopoietic cell transplant in high-risk neuroblastoma.
Biol Blood Marrow Transplant 2019; 25: 2031–39.
119 Epperla N, Li A, Logan B, et al. Incidence, risk factors for and
outcomes of transplant-associated thrombotic microangiopathy.
Br J Haematol 2020; 189: 1171–81.
120 Caires RA, Marques ID, Repizo LP, et al. De novo thrombotic
microangiopathy after kidney transplantation: clinical features,
treatment, and long-term patient and graft survival. Transplant Proc
2012; 44: 2388–90.
121 Jodele S, Laskin BL, Dandoy CE, et al. A new paradigm: diagnosis
and management of HSCT-associated thrombotic
microangiopathy as multi-system endothelial injury. Blood Rev
2015; 29: 191–204.
122 Kobayashi T, Wada H, Usui M, et al. Decreased ADAMTS13 levels
in patients after living donor liver transplantation. Thromb Res 2009;
124: 541–45.
123 Pereboom IT, Adelmeijer J, van Leeuwen Y, Hendriks HG, Porte RJ,
Lisman T. Development of a severe von Willebrand factor/
ADAMTS13 dysbalance during orthotopic liver transplantation.
Am J Transplant 2009; 9: 1189–96.
124 Young JA, Pallas CR, Knovich MA. Transplant-associated
thrombotic microangiopathy: theoretical considerations and a
practical approach to an unrefined diagnosis.
Bone Marrow Transplant 2021; 56: 1805–17.
125 Verbiest A, Pirenne J, Dierickx D. De novo thrombotic
microangiopathy after non-renal solid organ transplantation.
Blood Rev 2014; 28: 269–79.
126 Dvorak CC, Higham C, Shimano KA. Transplant-associated
thrombotic microangiopathy in pediatric hematopoietic cell
transplant recipients: a practical approach to diagnosis and
management. Front Pediatr 2019; 7: 133.
1737
 Seminar
127 Wirtschafter E, VanBeek C, Linhares Y. Bone marrow transplant-
associated thrombotic microangiopathy without peripheral blood
schistocytes: a case report and review of the literature.
Exp Hematol Oncol 2018; 7: 14.
128 Jodele S, Hirsch R, Laskin B, Davies S, Witte D, Chima R.
Pulmonary arterial hypertension in pediatric patients with
hematopoietic stem cell transplant-associated thrombotic
microangiopathy. Biol Blood Marrow Transplant 2013; 19: 202–07.
129 Sartain S, Shubert S, Wu MF, et al. Therapeutic plasma exchange does
not improve renal function in hematopoietic stem cell transplantation-
associated thrombotic microangiopathy: an institutional experience.
Biol Blood Marrow Transplant 2019; 25: 157–62.
130 Ho VT, Cutler C, Carter S, et al. Blood and marrow transplant
clinical trials network toxicity committee consensus summary:
thrombotic microangiopathy after hematopoietic stem cell
transplantation. Biol Blood Marrow Transplant 2005; 11: 571–75.
131 Ruutu T, Barosi G, Benjamin RJ, et al. Diagnostic criteria for
hematopoietic stem cell transplant-associated microangiopathy:
results of a consensus process by an International Working Group.
Haematologica 2007; 92: 95–100.
132 Cho BS, Yahng SA, Lee SE, et al. Validation of recently proposed
consensus criteria for thrombotic microangiopathy after allogeneic
hematopoietic stem-cell transplantation. Transplantation 2010;
90: 918–26.
133 Jodele S, Dandoy CE, Myers KC, et al. New approaches in the
diagnosis, pathophysiology, and treatment of pediatric
hematopoietic stem cell transplantation-associated thrombotic
microangiopathy. Transfus Apher Sci 2016; 54: 181–90.
134 Fujiwara H, Maeda Y, Sando Y, et al. Treatment of thrombotic
microangiopathy after hematopoietic stem cell transplantation with
recombinant human soluble thrombomodulin. Transfusion 2016;
56: 886–92.
135 Goodship THJ, Pinto F, Weston-Davies WH, et al. Use of the
complement inhibitor coversin to treat HSCT-associated TMA.
Blood Adv 2017; 1: 1254–58.
136 Yeates L, Slatter MA, Bonanomi S, et al. Use of defibrotide to treat
transplant-associated thrombotic microangiopathy: a retrospective
study of the Paediatric Diseases and Inborn Errors Working Parties
of the European Society of Blood and Marrow Transplantation.
Bone Marrow Transplant 2017; 52: 762–64.
137 Wolff D, Wilhelm S, Hahn J, et al. Replacement of calcineurin
inhibitors with daclizumab in patients with transplantation-
associated microangiopathy or renal insufficiency associated with
graft-versus-host disease. Bone Marrow Transplant 2006; 38: 445–51.
138 Togashi J, Sugawara Y, Akamatsu N, et al. A single-center
experience of the use of interleukin-2 receptor antagonists for
various situations in liver transplant recipients. Transplant Proc
2014; 46: 739–43.
139 Wilson CH, Brown AL, White SA, Goodship TH, Sheerin NS,
Manas DM. Successful treatment of de novo posttransplant
thrombotic microangiopathy with eculizumab. Transplantation 2011;
92: e42–43.
140 Cremer A, Amraoui F, Lip GY, et al. From malignant hypertension
to hypertension-MOD: a modern definition for an old but still
dangerous emergency. J Hum Hypertens 2016; 30: 463–66.
141 Timmermans SAME, Wérion A, Damoiseaux JGMC, Morelle J,
Reutelingsperger CP, van Paassen P. Diagnostic and risk factors for
complement defects in hypertensive emergency and thrombotic
microangiopathy. Hypertension 2020; 75: 422–30.
142 Babar F, Cohen SD. Thrombotic microangiopathies with
rheumatologic involvement. Rheum Dis Clin North Am 2018;
44: 635–49.
143 Thurman JM, Frazer-Abel A, Holers VM. The evolving landscape
for complement therapeutics in rheumatic and autoimmune
diseases. Arthritis Rheumatol 2017; 69: 2102–13.
144 Noris M, Remuzzi G. Genetics of immune-mediated glomerular
diseases: focus on complement. Semin Nephrol 2017; 37: 447–63.
145 Turrent-Carriles A, Herrera-Félix JP, Amigo MC. Renal involvement
in antiphospholipid syndrome. Front Immunol 2018; 9: 1008.
146 Fayyaz A, Igoe A, Kurien BT, et al. Haematological manifestations
of lupus. Lupus Sci Med 2015; 2: e000078.
147 Li J, Jiang JJ, Wang CY, et al. Clinical features and prognosis of
patients with thrombotic thrombocytopenic purpura associated with
systemic lupus erythematosus: a review of 25 cases. Ital J Pediatr
2019; 45: 55.
1738
148 Cavero T, Rabasco C, López A, et al. Eculizumab in secondary
atypical haemolytic uraemic syndrome. Nephrol Dial Transplant
2017; 32: 466–74.
149 Tinti MG, Carnevale V, Inglese M, et al. Eculizumab in refractory
catastrophic antiphospholipid syndrome: a case report and
systematic review of the literature. Clin Exp Med 2019; 19: 281–88.
150 Devresse A, Aydin S, Le Quintrec M, et al. Complement activation
and effect of eculizumab in scleroderma renal crisis. Medicine 2016;
95: e4459.
151 Thomas MR, Scully M. Microangiopathy in cancer: causes,
consequences, and management. Cancer Treat Res 2019;
179: 151–58.
152 Huber-Lang M, Sarma JV, Zetoune FS, et al. Generation of C5a in
the absence of C3: a new complement activation pathway. Nat Med
2006; 12: 682–87.
153 Brain MC, Azzopardi JG, Baker LR, Pineo GF, Roberts PD,
Dacie JV. Microangiopathic haemolytic anaemia and mucin-
forming adenocarcinoma. Br J Haematol 1970; 18: 183–93.
154 Lohrmann HP, Adam W, Heymer B, Kubanek B. Microangiopathic
hemolytic anemia in metastatic carcinoma. Report of eight cases.
Ann Intern Med 1973; 79: 368–75.
155 Antman KH, Skarin AT, Mayer RJ, Hargreaves HK, Canellos GP.
Microangiopathic hemolytic anemia and cancer: a review. Medicine
1979; 58: 377–84.
156 Coppola A, Davi G, De Stefano V, Mancini FP, Cerbone AM,
Di Minno G. Homocysteine, coagulation, platelet function,
and thrombosis. Semin Thromb Hemost 2000; 26: 243–54.
157 Ishida Y, Yamashita K, Sasaki H, et al. Activation of complement
system in adult T-cell leukemia (ATL) occurs mainly through lectin
pathway: a serum proteomic approach using mass spectrometry.
Cancer Lett 2008; 271: 167–77.
158 Weitz IC. Thrombotic microangiopathy in cancer.
Semin Thromb Hemost 2019; 45: 348–53.
159 Fakhouri F, Roumenina L, Provot F, et al. Pregnancy-associated
hemolytic uremic syndrome revisited in the era of complement
gene mutations. J Am Soc Nephrol 2010; 21: 859–67.
160 Dashe JS, Ramin SM, Cunningham FG. The long-term
consequences of thrombotic microangiopathy (thrombotic
thrombocytopenic purpura and hemolytic uremic syndrome) in
pregnancy. Obstet Gynecol 1998; 91: 662–68.
161 Fakhouri F, Vercel C, Frémeaux-Bacchi V. Obstetric nephrology:
AKI and thrombotic microangiopathies in pregnancy.
Clin J Am Soc Nephrol 2012; 7: 2100–06.
162 Fakhouri F, Scully M, Provôt F, et al. Management of thrombotic
microangiopathy in pregnancy and postpartum: report from an
international working group. Blood 2020; 136: 2103–17.
163 Nikuei P, Rajaei M, Roozbeh N, et al. Diagnostic accuracy of
sFlt1/PlGF ratio as a marker for preeclampsia. BMC Pregnancy
Childbirth 2020; 20: 80.
164 Amari Chinchilla K, Vijayan M, Taveras Garcia B, Jim B.
Complement-mediated disorders in pregnancy.
Adv Chronic Kidney Dis 2020; 27: 155–64.
165 Kumar D, King M, Jim B, Acharya A. Recurrent case of pregnancy-
induced atypical haemolytic uremic syndrome (P-aHUS).
BMJ Case Rep 2019; 12: bcr-2018-226571.
166 Chatzikonstantinou T, Gavriilaki M, Anagnostopoulos A,
Gavriilaki E. An update in drug-induced thrombotic
microangiopathy. Front Med 2020; 7: 212.
167 Zakarija A, Bennett C. Drug-induced thrombotic microangiopathy.
Semin Thromb Hemost 2005; 31: 681–90.
168 Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and
renal thrombotic microangiopathy. N Engl J Med 2008; 358: 1129–36.
169 Page EE, Little DJ, Vesely SK, George JN. Quinine-induced
thrombotic microangiopathy: a report of 19 patients.
Am J Kidney Dis 2017; 70: 686–95.
170 Saleem R, Reese JA, George JN. Drug-induced thrombotic
microangiopathy: an updated systematic review, 2014–2018.
Am J Hematol 2018; 93: E241–43.
171 Al-Nouri ZL, Reese JA, Terrell DR, Vesely SK, George JN.
Drug-induced thrombotic microangiopathy: a systematic review of
published reports. Blood 2015; 125: 616–18.
172 Campistol JM, Arias M, Ariceta G, et al. An update for atypical
haemolytic uraemic syndrome: diagnosis and treatment.
A consensus document. Nefrologia 2013; 33: 27–45.
www.thelancet.com Vol 400 November 12, 2022

173 Azoulay E, Knoebl P, Garnacho-Montero J, et al. Expert
statements on the standard of care in critically ill adult patients
with atypical hemolytic uremic syndrome. Chest 2017;
152: 424–34.
174 Grisaru S, Xie J, Samuel S, et al. Associations between hydration
status, intravenous fluid administration, and outcomes of patients
infected with Shiga toxin-producing Escherichia coli: a systematic
review and meta-analysis. JAMA Pediatr 2017; 171: 68–76.
175 Freedman SB, Xie J, Neufeld MS, et al. Shiga toxin-producing
Escherichia coli infection, antibiotics, and risk of developing hemolytic
uremic syndrome: a meta-analysis. Clin Infect Dis 2016; 62: 1251–58.
176 Kakoullis L, Papachristodoulou E, Chra P, Panos G. Shiga toxin-
induced haemolytic uraemic syndrome and the role of antibiotics:
a global overview. J Infect 2019; 79: 75–94.
177 Tarr PI, Freedman SB. Why antibiotics should not be used to treat
Shiga toxin-producing Escherichia coli infections.
Curr Opin Gastroenterol 2022; 38: 30–38.
178 Schwartz J, Padmanabhan A, Aqui N, et al. Guidelines on the use of
therapeutic apheresis in clinical practice-evidence-based approach
from the writing committee of the American Society for Apheresis:
the seventh special issue. J Clin Apher 2016; 31: 149–62.
179 Kielstein JT, Beutel G, Fleig S, et al. Best supportive care and
therapeutic plasma exchange with or without eculizumab in Shiga-
toxin-producing E. coli O104:H4 induced haemolytic-uraemic
syndrome: an analysis of the German STEC-HUS registry.
Nephrol Dial Transplant 2012; 27: 3807–15.
180 Lapeyraque AL, Malina M, Fremeaux-Bacchi V, et al. Eculizumab in
severe Shiga-toxin-associated HUS. N Engl J Med 2011; 364: 2561–63.
181 Mahat U, Matar RB, Rotz SJ. Use of complement monoclonal
antibody eculizumab in Shiga toxin producing Escherichia coli
associated hemolytic uremic syndrome: a review of current
evidence. Pediatr Blood Cancer 2019; 66: e27913.
182 Michael M, Elliott EJ, Ridley GF, Hodson EM, Craig JC. Interventions
for haemolytic uraemic syndrome and thrombotic thrombocytopenic
purpura. Cochrane Database Syst Rev 2009; 2009: CD003595.
183 Hopkins CK, Yuan S, Lu Q, Ziman A, Goldfinger D. A severe case
of atypical hemolytic uremic syndrome associated with
pneumococcal infection and T activation treated successfully with
plasma exchange. Transfusion 2008; 48: 2448–52.
184 Weintraub L, Ahluwalia M, Dogra S, Uehlinger J, Skversky A,
Vasovic L. Management of streptococcal pneumoniae-induced
hemolytic uremic syndrome: a case report. Clin Nephrol Case Stud
2014; 2: 9–17.
185 Rother RP, Rollins SA, Mojcik CF, Brodsky RA, Bell L. Discovery
and development of the complement inhibitor eculizumab for the
treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol
2007; 25: 1256–64.
186 Licht C, Greenbaum LA, Muus P, et al. Efficacy and safety of
eculizumab in atypical hemolytic uremic syndrome from 2-year
extensions of phase 2 studies. Kidney Int 2015; 87: 1061–73.
187 Menne J, Delmas Y, Fakhouri F, et al. Outcomes in patients with
atypical hemolytic uremic syndrome treated with eculizumab in a
long-term observational study. BMC Nephrol 2019; 20: 125.
188 Rondeau E, Scully M, Ariceta G, et al. The long-acting C5 inhibitor,
ravulizumab, is effective and safe in adult patients with atypical
hemolytic uremic syndrome naïve to complement inhibitor
treatment. Kidney Int 2020; 97: 1287–96.
189 Tanaka K, Adams B, Aris AM, et al. The long-acting C5 inhibitor,
ravulizumab, is efficacious and safe in pediatric patients with
atypical hemolytic uremic syndrome previously treated with
eculizumab. Pediatr Nephrol 2021; 36: 889–98.
190 Hayes W, Tschumi S, Ling SC, Feber J, Kirschfink M, Licht C.
Eculizumab hepatotoxicity in pediatric aHUS. Pediatr Nephrol 2015;
30: 775–81.
191 Oruc A, Ayar Y, Vuruskan BA, et al. Hepatotoxicity associated with
eculizumab in a patient with atypical hemolytic uremic syndrome.
Nefrologia 2018; 38: 448–50.
192 Ardissino G, Testa S, Possenti I, et al. Discontinuation of
eculizumab maintenance treatment for atypical hemolytic uremic
syndrome: a report of 10 cases. Am J Kidney Dis 2014; 64: 633–7.
193 Fakhouri F, Fila M, Provôt F, et al. Pathogenic variants in
complement genes and risk of atypical hemolytic uremic syndrome
relapse after eculizumab discontinuation. Clin J Am Soc Nephrol
2017; 12: 50–59.
www.thelancet.com Vol 400 November 12, 2022
Seminar
194 Wijnsma KL, Duineveld C, Wetzels JFM, van de Kar NCAJ.
Eculizumab in atypical hemolytic uremic syndrome: strategies
toward restrictive use. Pediatr Nephrol 2019; 34: 2261–77.
195 Merrill SA, Brittingham ZD, Yuan X, Moliterno AR, Sperati CJ,
Brodsky RA. Eculizumab cessation in atypical hemolytic uremic
syndrome. Blood 2017; 130: 368–72.
196 Fakhouri F, Fila M, Hummel A, et al. Eculizumab discontinuation
in children and adults with atypical hemolytic-uremic syndrome:
a prospective multicenter study. Blood 2021; 137: 2438–49.
197 Cugno M, Gualtierotti R, Possenti I, et al. Complement functional
tests for monitoring eculizumab treatment in patients with atypical
hemolytic uremic syndrome. J Thromb Haemost 2014; 12: 1440–48.
198 Ardissino G, Tel F, Sgarbanti M, et al. Complement functional tests
for monitoring eculizumab treatment in patients with atypical
hemolytic uremic syndrome: an update. Pediatr Nephrol
2018; 33: 457–61.
199 Gatault P, Brachet G, Ternant D, et al. Therapeutic drug monitoring
of eculizumab: rationale for an individualized dosing schedule.
MAbs 2015; 7: 1205–11.
200 Volokhina E, Wijnsma K, van der Molen R, et al. Eculizumab
dosing regimen in atypical HUS: possibilities for individualized
treatment. Clin Pharmacol Ther 2017; 102: 671–78.
201 Padmanabhan A, Connelly-Smith L, Aqui N, et al. Guidelines on
the use of therapeutic apheresis in clinical practice – evidence-
based approach from the Writing Committee of the American
Society for Apheresis: the eighth special issue. J Clin Apher 2019;
34: 171–354.
202 Igarashi T, Ito S, Sako M, et al. Guidelines for the management and
investigation of hemolytic uremic syndrome. Clin Exp Nephrol 2014;
18: 525–57.
203 Zuber J, Frimat M, Caillard S, et al. Use of highly individualized
complement blockade has revolutionized clinical outcomes after
kidney transplantation and renal epidemiology of atypical hemolytic
uremic syndrome. J Am Soc Nephrol 2019; 30: 2449–63.
204 Goodship TH, Cook HT, Fakhouri F, et al. Atypical hemolytic
uremic syndrome and C3 glomerulopathy: conclusions from
a “Kidney Disease: Improving Global Outcomes” (KDIGO)
controversies conference. Kidney Int 2017; 91: 539–51.
205 Siedlecki AM, Isbel N, Vande Walle J, James Eggleston J, Cohen DJ,
Global aHUS Registry. Eculizumab use for kidney transplantation
in patients with a diagnosis of atypical hemolytic uremic syndrome.
Kidney Int Rep 2019; 4: 434–46.
206 Kurup M, Mandelbrot D, Garg N, Singh T. Living related donor
kidney transplantation in atypical HUS: when should it be
considered? Kidney 2021; 360: 524–27.
207 de Fontbrune FS, Galambrun C, Sirvent A, et al. Use of eculizumab
in patients with allogeneic stem cell transplant-associated
thrombotic microangiopathy: a study from the SFGM-TC.
Transplantation 2015; 99: 1953–59.
208 Vasu S, Wu H, Satoskar A, et al. Eculizumab therapy in adults with
allogeneic hematopoietic cell transplant-associated thrombotic
microangiopathy. Bone Marrow Transplant 2016; 51: 1241–44.
209 Rudoni J, Jan A, Hosing C, Aung F, Yeh J. Eculizumab for transplant-
associated thrombotic microangiopathy in adult allogeneic stem cell
transplant recipients. Eur J Haematol 2018; 101: 389–98.
210 Bohl SR, Kuchenbauer F, von Harsdorf S, et al. Thrombotic
microangiopathy after allogeneic stem cell transplantation:
a comparison of eculizumab therapy and conventional therapy.
Biol Blood Marrow Transplant 2017; 23: 2172–77.
211 Jodele S, Dandoy CE, Myers KC, et al. New approaches in the
diagnosis, pathophysiology, and treatment of pediatric
hematopoietic stem cell transplantation-associated thrombotic
microangiopathy. Transfus Apher Sci 2016; 54: 181–90.
212 Jodele S, Fukuda T, Vinks A, et al. Eculizumab therapy in children
with severe hematopoietic stem cell transplantation-associated
thrombotic microangiopathy. Biol Blood Marrow Transplant 2014;
20: 518–25.
213 Jodele S, Dandoy CE, Lane A, et al. Complement blockade for TA-
TMA: lessons learned from a large pediatric cohort treated with
eculizumab. Blood 2020; 135: 1049–57.
214 Goodship THJ, Pinto F, Weston-Davies WH, et al. Use of the
complement inhibitor coversin to treat HSCT-associated TMA.
Blood Adv 2017; 1: 1254–58.
1739
 Seminar
215 Khaled SK, Claes K, Goh YT, et al. Narsoplimab, a mannan-binding
lectin-associated serine protease-2 inhibitor, for the treatment of
adult hematopoietic stem-cell transplantation-associated thrombotic
microangiopathy. J Clin Oncol 2022; 40: 2447–57.
216 Nishimura J, Yamamoto M, Hayashi S, et al. Genetic variants in C5
and poor response to eculizumab. N Engl J Med 2014; 370: 632–39.
217 Griffin M, Kelly R, Pike A. A review of the treatment landscape in
paroxysmal nocturnal haemoglobinuria: where are we now and
where are we going? Ther Adv Rare Dis 2020; 1: 1–12.
1740
218 Top O, Parsons J, Bohlender LL, et al. Recombinant production of
MFHR1, a novel synthetic multitarget complement inhibitor,
in moss bioreactors. Front Plant Sci 2019; 10: 260.
219 Michelfelder S, Fischer F, Wäldin A, et al. The MFHR1 fusion
protein is a novel synthetic multitarget complement inhibitor with
therapeutic potential. J Am Soc Nephrol 2018; 29: 1141–53.
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