Hemolytic-Uremic Syndrome in Children

H e m o l y t i c - U re m i c S y n d ro m e
in Children
a,b a,
Olivia Boyer, MD, PhD , Patrick Niaudet, MD, PhD *
KEYWORDS
Hemolytic uremic syndrome Thrombotic microangiopathy Shiga toxin
Alternative pathway of complement Eculizumab
KEY POINTS
Hemolytic uremic syndrome (HUS) is the leading cause of acute kidney injury in children.
Most cases are caused by Shiga-toxin-producing bacteria, especially Escherichia coli
(STEC-HUS).
Immediate outcome in STEC-HUS is often favorable but long-term renal sequelae are
frequent and follow-up is necessary.
Prevention of STEC-HUS relies on avoidance of undercooked bovine meat and unpas-
teurized dairy products, particularly before the age of 5 years.
Atypical HUS (aHUS), which accounts for about 5% of cases, is mostly due to genetic
and/or acquired abnormalities of the complement system.
aHUS has a relapsing course with high risk of death, kidney failure and recurrence after
renal transplantation.
The hemolytic uremic syndrome (HUS), defined by the simultaneous occurrence of

microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, is
a form of thrombotic microangiopathy affecting primarily the kidney.1 The most
common cause is HUS associated with Shiga toxin (Stx)-producing Escherichia
coli infection (STEC-HUS). Other infections may cause HUS, and these include
streptococcus pneumoniae and human immunodeficiency virus (HIV). Other causes
of HUS, previously referred to as atypical HUS, include hereditary causes mainly
due to complement gene variants, drug toxicity, and autoimmune diseases. A
new classification of HUS based on the underlying mechanisms was recently pro-
posed (Fig. 1).2
a
Pediatric Nephrology, Necker Enfants Malades Hospital, Université Paris Cité, France;
b
Néphrologie Pédiatrique, Hôpital Necker, 149 Rue de Sèvres, Paris 75015, France
* Corresponding author. Néphrologie Pédiatrique, Hôpital Necker, 149 Rue de Sèvres, Paris
75015, France.
E-mail address: pniaudet@gmail.com
Pediatr Clin N Am 69 (2022) 1181–1197

https://doi.org/10.1016/j.pcl.2022.07.006 pediatric.theclinics.com
0031-3955/22/ª 2022 Elsevier Inc. All rights reserved.
Descargado para Paula Andrea Murillo (pamurillotorres@gmail.com) en New Granada Military

University de ClinicalKey.es por Elsevier en febrero 01, 2023. Para uso personal exclusivamente. No se
permiten otros usos sin autorización. Copyright ©2023. Elsevier Inc. Todos los derechos reservados.
1182 Boyer & Niaudet
Fig. 1. Classification of various forms of hemolytic uremic syndrome. Reprinted with permis-
sion from Elsevier. The Lancet, Vol 390, Issue 10095, p,.681-696, Fadi Fakhouri et al., “Hae-
molytic uraemic syndrome”, 2017. https://doi.org/10.1016/S0140-6736(17)30062-4.
INFECTION-INDUCED HEMOLYTIC UREMIC SYNDROME
HUS may occur following STEC or streptococcus pneumoniae infection and rarely
with HIV, H1N1 influenza A, and SARS-CoV2 infections.
STEC-HUS
STEC-HUS is the most common form of HUS in children accounting for 90% of all
cases. HUS develops in approximately 15% of children with STEC infection.
Epidemiology
Different E coli strains have been associated with both sporadic and epidemic STEC-
HUS cases throughout the world. There are 2 clinically relevant categories of STEC:
those that contain a gene encoding Stx 2 (with or without a gene encoding Stx1)
and those that do not. Stx2 is associated with more severe forms of HUS.
The E coli serotype associated with HUS varies regionally and over time. In the United
States and in Europe, E coli O157:H7 has been the most frequent strain associated with
HUS in children. Almost all E coli O157:H7 contain a gene encoding Stx 2. However,
other strains have become more common, including O26, O111, O121, O145, O91,
O103, O104, and O80.3 In Latin America, E coli O157:H7 remains the predominant strain
(>70%). In Australia, approximately one-half of cases are due to E coli 0111.

Hemolytic-Uremic Syndrome 1183
Although found in other animals, healthy cattle are the main vectors of STEC, with
the bacteria being present in their intestine and feces.4 Infection in humans occurs
following ingestion of contaminated undercooked meat; unpasteurized milk or milk
products; and contaminated water, fruits, or vegetables.5 Secondary human to human
contamination is also possible and may be a concern in day-care centers or in siblings.
Shigella dysenteriae type 1–associated HUS, also due to Shiga toxins, occurs in In-
dia, Bangladesh, and Southern Africa. Although the pathogenesis of disease is similar
to that of HUS induced by E coli infection, the disease is usually more severe with an
acute mortality rate of 15%, and greater than 40% of patients develop chronic kidney
disease.
Pathophysiology
Stx-mediated injury to vascular endothelial cells in the kidney, brain, and other organs
underlies the pathogenesis of HUS caused by STEC. These potent cytotoxins that are
released in the gut by bacteria enter the blood stream and cause endothelial injury by
binding to the globotriaosylceramide (Gb3) receptor on plasma membrane of the
target cells.6 In humans, Gb3 is a sphingolipid receptor expressed on endothelial cells,
podocytes, and proximal tubular cells. Stx binding to Gb3 leads to Stx internalization
by receptor-mediated endocytosis and its retrograde transport to the endoplasmic re-
ticulum; this triggers a cascade of signaling events, involving NF-kB activation, which
induces apoptosis and the binding of leukocytes to endothelial cells.7 Activated endo-
thelial cells become thrombogenic, initiating microvascular thrombus formation. In
addition, Stxs activate complement and platelet thrombus formation on the endothe-
lial cells.
Clinical manifestations
STEC-HUS principally affects children younger than 5 years. It usually occurs after a
prodromal illness with abdominal pain, vomiting, and diarrhea that is frequently
bloody. Five to ten days later, HUS develops with the onset of microangiopathic he-
molytic anemia with fragmented erythrocytes called schistocytes (Fig. 2) and negative
Coombs tests, thrombocytopenia, and acute kidney injury. Despite thrombocyto-
penia, there is usually no purpura or active bleeding. Although the degree of anemia
or thrombocytopenia is unrelated to the severity of kidney dysfunction, an increased
white blood cell count is associated with a worse prognosis. The hematologic mani-
festations of STEC-HUS usually resolve completely within 1 to 2 weeks. The kidney
involvement ranges from hematuria, usually microscopic, and proteinuria, to severe
kidney failure and oligoanuria that occurs in one-half of the cases. Hypertension is
Fig. 2. Red blood cell fragmentation (schistocytes).

common. Dialysis is required in as many as 50% of children during the acute phase,
for a mean period of 10 days. The short-term renal prognosis is generally favorable.
However, the risk of kidney failure 20 years after the recovery of STEC-HUS is not
negligible, and kidney histology showing glomerular microangiopathy affecting greater
than 50% of glomeruli (Fig. 3), arterial microangiopathy, and/or cortical necrosis
(Fig. 4) at disease onset indicates a poorer long-term prognosis.
STEC-HUS often affects other organ systems (Fig. 5).8 Central nervous system
involvement, which occurs in 20% to -50% of children, is the most serious complication
associated with increased morbidity and mortality.9 Patients may present with seizures,
coma, stroke, hemiparesis, facial palsy, pyramidal or extrapyramidal syndromes,
dysphasia, diplopia, and cortical blindness. Brain MRI typically reveals bilateral hyper-
intensity on T2-weighted and hypointensity on T1-weighted images of basal ganglia,
thalami, and brainstem, sometimes extending to the surrounding white matter. In addi-
tion, MRI may display images of high blood pressure complications such as reversible
posterior leukoencephalopathy syndrome and cerebral hemorrhage.
Gastrointestinal manifestations include severe hemorrhagic colitis, bowel necrosis
and perforation, rectal prolapse, peritonitis, and intussusception. Cardiac ischemia
and dysfunction may occur. Transient and rarely permanent diabetes mellitus may
occur. Hepatomegaly and/or increased serum transaminases are frequently
observed. Over the years, the mortality rate has dropped to about 5% and is mostly
due to neurologic or cardiac involvement.10 Persistent oligoanuria (>5 days of anuria
and >10 days of oliguria), dehydration, elevated white blood cell count greater than
20,000 per mm3, and hematocrit greater than 23% are other risk factors for mortality
and long-term complications from HUS.
The evaluation for STEC infection includes testing for Stxs (polymerase chain reac-
tion for the presence of ST-1 and/or ST-2 genes) in the stool and stool cultures. Re-
sults from stool cultures may be unreliable because the bacteria are present in stool
for a few days only and, even if present, may not be detected by culture from stool
samples. Serum antibodies to lipopolysaccharide of STEC persist for several weeks
and may be of added value in the diagnosis of STEC infection.
Treatment
Patients with HUS can become profoundly anemic very quickly. Packed red blood cells
should be transfused when the hemoglobin level is less than 6 g/dL or hematocrit less
Fig. 3. Thrombotic microangiopathy: “double contour” appearance of the capillary walls

with a widening of the subendothelial space. These lesions affect a variable proportion
of glomeruli.

Fig. 4. Cortical necrosis.
than 18% to avoid cardiovascular and pulmonary complications. The goal is not to
restore the hemoglobin level to normal because the increased volume may cause heart
failure, pulmonary edema, and hypertension. Blood products should be volume reduced
and preferably depleted of leukocytes and platelets to avoid alloimmunization.
Platelet transfusion is reserved for patients with clinically significant bleeding or if an
invasive procedure is required. Significant bleeding is infrequent because the platelet
count rarely falls less than 10,000/mm3, and platelet production and function are
normal. Platelet transfusion may induce antihuman leukocyte antigen antibodies,
which may be deleterious later if the patient progresses to end-stage kidney failure
and requires kidney transplantation.
Fluid management is based on the intravascular volume status of the patient and
kidney function. Patients with decreased intravascular volume are repleted to a euvo-
lemic state, whereas those with increased intravascular volume and diminished urine
Fig. 5. Complement pathway. The black loop represents the complement amplification
loop. Black stars represent known genes which mutations cause aHUS. Black squares indi-
cate drugs targeting the complement system, used in aHUS. CFB, complement factor B;
CFD, complement factor D; CFH, complement factor H; CFI, complement factor I; MAC, mem-
brane attack complex; MCP, membrane cofactor protein; THBD, thrombomodulin.

output are fluid restricted. Observational studies have reported that an early volume
expansion may reduce the risk of CNS involvement, need of kidney replacement ther-
apy, and long-term renal sequelae.
There is no evidence that early dialysis affects the clinical outcome. As a result, the
indications for dialysis in children with HUS are similar to those in children with other
forms of acute kidney injury. In most young children, peritoneal dialysis is preferred.
However, there is no evidence of increased benefit of peritoneal dialysis as compared
with hemodialysis.
Management of hypertension is directed toward correcting the fluid status and us-
ing antihypertensive agents such as the calcium channel blockers. Randomized trials
have not shown any benefits from antithrombotic or antifibrinolytic agents, plasma in-
fusions, tissue-type plasminogen activator, and oral Stx-binding agents.1 Patients
with severe neurological manifestations may be treated with eculizumab11,12 and
immunoadsorption if they do not respond to eculizumab.13
Prevention
Prevention of STEC-HUS rests in part on measures aimed at reducing the risk of STEC
infection. These measures include meticulous hygiene when cooking and changing di-
apers and avoidance of undercooked meat and unpasteurized milk products in young
children. STEC infection may also occur through water contamination, direct contact
with infected animals, or person–person spread.
Several studies have provided evidence supporting the possibility of preventing or
reducing the severity of HUS by early intravascular volume expansion with intravenous
isotonic solutions in patients with STEC who are volume depleted.14 Once a patient is
infected with STEC, attempts to prevent progression from the bloody diarrheal phase
to the HUS have been unsuccessful. Administration of antimotility drugs (such as anti-
cholinergic agents or narcotics) do not reduce the progression to HUS caused by
STEC infection, but on the contrary seem to increase the risk for HUS.15 The impact
of antibiotic administration during the bloody diarrheal phase remains uncertain. There
are clinical observational data that suggest administration of beta-lactams, and
trimethoprim/sulfamethoxazole is associated with increased risk of developing
HUS,16 whereas fosfomycin may reduce the risk for HUS.17
Pneumococcal-Associated Hemolytic Uremic Syndrome

Pneumococcal-associated HUS accounts for about 5% of all childhood cases of HUS.
Patients present with pneumonia (70%) or meningitis (20%–30%). In comparison to
STEC HUS, children with pneumococcal-associated HUS are younger, have more se-
vere disease onset with longer duration of oliguria and thrombocytopenia, and are
likely to require more blood transfusions.18
The pathogenesis of this form of HUS remains unclear. It has been proposed that
desialylation by neuraminidase results in exposing the Thomsen-Friedenreich antigen
(T antigen) on red blood cells, platelets, and glomeruli, resulting in polyagglutination of pa-
tient’s red cells and hemolysis.19 In addition, an activation of the alternative pathway
probably plays a role.20
The management of pneumococcal-associated HUS is supportive. In addition,
empiric antibiotic therapy for invasive pneumococcal disease should be initiated
with both vancomycin and a broad-spectrum cephalosporin. It is recommended to
avoid plasma infusion or plasmapheresis because of concerns that plasma, which
contains natural immunoglobulin M (IgM) class antibodies to the Thomsen-
Friedenreich antigen, may aggravate hemolysis.21 The mortality related to the

underlying infection and the long-term risk of chronic kidney disease is higher as
compared with patients with STEC HUS.
ATYPICAL HEMOLYTIC UREMIC SYNDROME
Atypical hemolytic uremic syndrome (aHUS) is a heterogeneous group of disorders

that includes all forms of HUS that are not caused by infections or coexisting medical
conditions.2 It is a rare condition with an estimated incidence of 0.25 to 2 per million
per year and accounts for 10% of all cases of HUS diagnosed in childhood.22 The pro-
posed mechanism for complement-mediated aHUS is the unregulated activation of
the complement system triggered by infections, immunizations, or pregnancy, in a
susceptible individual with inherited (genetic) or acquired (autoimmune) disruption of
the alternate complement pathway (Fig. 6). An uninhibited continuous activation of
the alternative pathway with subsequent formation of the membrane attack complex
on endothelial cells, red blood cells, and platelets causes renal and extrarenal endo-
thelial damage, activation of the coagulation cascade, and thrombotic
microangiopathy.23
Nowadays, a hereditary abnormality in the alternative complement pathway is iden-
tified in approximately 60% of the patients with aHUS.24 Other hereditary causes of
complement-independent aHUS have been described. These include intracellular de-
fects of vitamin B12 or lipid metabolisms. Untreated, aHUS has a poor prognosis with
high risk of relapses, progression to kidney failure, and a significant mortality, risks that
Fig. 6. Clinical presentation and evolution of STEC-HUS.

vary depending on the underlying cause.25 Extrarenal manifestations of aHUS are

frequent in children.26 These include neurological involvement in up to 27% of cases,
cardiovascular complications in 7%, and gastrointestinal symptoms in 10% to 80% of
cases, which seem to be particularly frequent in case of anticomplement factor H
(CFH) antibodies.27
Given the frequency of prodromal diarrhea in children with aHUS, it may be difficult
to differentiate typical and atypical HUS at the disease onset.25 The diagnostic workup
should include a detailed assessment of complement function, including a CH50
assay (a functional hemolytic test that explores the classic and common final path-
ways) combined with a quantitative measurement of C3 and C4 fractions, factor H,
factor B, and factor I proteins, and study of CD46 expression on the cell surface.2
In addition, anti-factor H autoantibody detection should be performed urgently, as
identification of high levels would require specific therapy. Genetic testing in patients
with aHUS is essential for prognostic assessment and necessary for the long-term
treatment of patients, as it may guide treatment duration.2 Differential diagnoses
such as ADAMTS13 deficiency or autoantibodies should also be promptly ruled out.
Complement Gene Variants

Complement acts as a major defense system against microorganisms in humans
through spontaneous hydrolysis of C3 and deposition of C3b on multiple cells that
are in contact with the plasma. Because of its permanent activation and amplification
ability, complement system needs to be finely regulated so that its activation occurs
only at the microbial surfaces but is inhibited at intact host cell surfaces. The variants
causing aHUS ultimately lead to a permanent and uncontrolled activation of the alter-
native pathway of complement and thereby damage to host cells.
Genetically predisposed aHUS may occur due to loss-of-function variants of inhib-
itory genes (eg, CFH, CFI, MCP, or THBD) or gain-of-function variants in activating
genes (eg, CFB and C3).28 Even in these inherited conditions, aHUS can manifest at
any age on triggering events. The predominant mode of inheritance is autosomal
dominance, although a subset of patients has homozygous CFH or CD46 variants
and typically have earlier disease onset and more severe phenotypes. The penetrance
of the disease is low, as less than 20% of family members, carrying the same variant
as the patient, present with aHUS manifestations.29
CFH gene variants (encoding complement factor H, reported mutation frequency

20%–30%)
CFH encodes complement factor H, a complement alternative pathway inhibitor in the
fluid phase and on cell surfaces. It binds to C3b, accelerates the decay of the C3bBb
convertase, and also serves as a cofactor for complement factor I, another C3b inhib-
itor. CFH is the most frequently mutated gene in patients with aHUS, accounting for
approximately 20% to 30% of all incident patients.22,30 CFH pathogenic variants
have been identified in approximately 25% of sporadic cases and 40% of familial
aHUS cases.31 They are distributed throughout the gene, but most are found in the
carboxy-terminus, encoding short consensus repeats 19 and 20 that bind C3b32
and endothelia.33 Some variants cause a quantitative deficiency of protein in the
plasma, whereas others induce a functional defect of the protein even when the level
is normal.
The aHUS manifestations typically occur either before the age of 4 years or in the
second to fourth decades.30 Homozygous CFH variants are almost exclusively seen
in infants, and heterozygous variants are found in all age groups, usually with incom-
plete penetrance.34 Severe hypertension is commonly observed. Hemolytic anemia is

marked at disease onset and during relapses, with haptoglobin and CH50 levels
remaining low throughout the course of the disease. Among all aHUS patients, those
with CFH variants have the worst outcome with the highest risk of developing kidney
failure or death within one year of diagnosis.35 Moreover, they have a high risk of post-
kidney transplant recurrence and poor allograft survival in the absence of specific
treatment.30
CD46 gene variants (previously known as membrane cofactor protein, 5%–15%)

CD46 (or membrane cofactor protein [MCP]) is a cofactor of complement factor I in the
degradation of C3b. The mutations causing aHUS most commonly result in decreased
cell surface levels of CD46 or a reduced ability to control activation of the alternative
complement pathway on host cells without quantitative deficiency.36 CD46-
associated aHUS is characterized by an early onset in childhood, frequent relapses,
a favorable renal course in most patients, and a low recurrence rate in the kidney
allograft.37
CFI gene variants (complement factor I, 5%–10%)

Complement factor I inactivates C3b fragments by proteolytic cleavage in the pres-
ence of its serum cofactor (factor H) or membrane cofactor (CD46). The products of
C3b degradation are unable to reconstitute a C3 convertase. Most patients bear het-
erozygous CFI variants, yielding a quantitative or qualitative factor I defect.38,39 Of
note, an additional genetic risk factor for HUS is sometimes identified in patients
with CFI variants.40 aHUS associated with CFI variants are less severe than aHUS
related to CFH variants but more severe than aHUS due to CD46 variants. The re-
ported progression to kidney failure is 50% to 60% within 2 years of presentation,40,41
with one-third of patients recovering from the initial thrombotic microangiopathy pre-
sentation without disease recurrence.40 Recurrence occurs after kidney transplanta-
tion in 45% to 80% of patients and ultimately leads to graft loss.
C3 gene variants (complement factor 3, 4%–7%)

Although these variants are spread throughout the protein, there is a reported cluster
in the thioester-containing domain that is essential for C3 activation.40 Similar to pa-
tients with CFH-related aHUS, the renal prognosis of aHUS caused by C3 variants
is guarded in the absence of specific treatment.42
CFB gene variants (complement factor B, 1%–2%)

Gain-of-function CFB variants have been more rarely reported, either enhancing for-
mation or delaying inactivation of the C3bBb convertase. They are associated with
progression to kidney failure in 70% of patients, a very high risk of posttransplant
aHUS recurrence and subsequent graft loss.43,44
THBD gene variants (thrombomodulin, 0%–5%)

Thrombomodulin serves as a cofactor for thrombin-catalyzed activation of protein C
and is a natural anticoagulant. In addition, it enhances complement factor I–
mediated degradation of C3b. One study reported 6 heterozygous THBD gene vari-
ants in 7 patients in a cohort of 152 patients with aHUS (5%). In vitro functional studies
demonstrated that thrombomodulin mutants were less effective in inactivating C3b
than the normal protein and resulted in deregulation of the complement system.
Nevertheless, pathogenic variants in this gene have rarely been found by other groups,
and their pathogenicity is still a matter of debate. Whether eculizumab is efficient in
such cases deserves clarification.

Treatment
Symptomatic treatment is similar to STEC-HUS as detailed earlier.
Plasma therapy was once the cornerstone for the treatment of aHUS, despite the
lack of a high level of evidence for its efficacy. The advantages of plasma exchanges
compared with plasma infusion included removal of defective mutant proteins and au-
toantibodies, administration of functioning complement proteins, and a lower risk of
volume overload and hypertension in patients with acute kidney injury. However,
this treatment was suboptimal, given the low remission rate in less than 50% of pa-
tients and the high morbidity and mortality rates depending on the affected comple-
ment gene.35,45,46 Indeed, the incidence of kidney failure or death was
approximately 40% at onset and 65% within 1 year.47 The remission rate was higher
in cases of CFH variants than with CFI or MCP variants. The procedure was some-
times tolerated poorly with frequent allergic reactions, and its long-term hospital-
based administration had a negative impact on the quality of life, schooling, and social
activities of children.
The prognosis of aHUS has improved considerably with the advent of complement
inhibitors. The first to be approved for this indication was eculizumab in 2011.47 Ecu-
lizumab is a recombinant humanized monoclonal anti-C5 antibody that inhibits the
terminal part of the complement pathway, from the formation of C5a to the
membrane-attack-complex assemblage. In the majority of children treated with ecu-
lizumab, the reported outcome is favorable in both acute and chronic settings with a
rapid and sustained improvement of hematological and renal parameters during the
first and subsequent episodes of aHUS, including those occurring after renal trans-
plantation.48,49 Consequently, in 2014 an international consensus recommended its
use as first-line treatment in children with a clinical diagnosis of aHUS.2 It should be
started promptly within 24 to 48 hours of diagnosis, as early initiation is associated
with better recovery of kidney function. It is not necessary to wait for the results of ge-
netic testing to initiate treatment, as this can take a long time, and eculizumab is effec-
tive in a number of children without any identified genetic variants. Currently, there are
2 drugs that act by targeting and inhibiting the C5/C5a axis and are suitable for the
treatment of aHUS and these include eculizumab, and ravulizumab.50 Other drugs
are being investigated.
The most frequent and potentially fatal side effects of complement inhibitors are in-
fections and in particular meningococcal meningitis. Children treated with complement
blockers should therefore be vaccinated against all strains of meningococcus and pneu-
mococcus, at best before the initiation of treatment, and receive antibiotic prophylaxis.
With these precautions, drug-related infections are rare, and patients recover without
any sequelae. Hepatotoxicity has also been reported but it is difficult to determine
whether it is treatment related or related to preexisting hepatic thrombotic microangiop-
athy; this suggests an overall favorable risk profile for eculizumab.2,47,48
Considering the prohibitive cost, twice-monthly intravenous administration, and
high infectious risks, several studies have investigated the safety of dose spacing or
discontinuation of eculizumab in selected patients.51 Fakhouri and colleagues52
demonstrated in a prospective trial that eculizumab can be stopped safely in the
absence of any causal variant or in the case of a MCP variant, provided that the re-
lapses are closely monitored, and eculizumab restarted promptly in case of confirmed
relapse. This study also revealed that restarting eculizumab promptly at the onset of a
relapse was associated with a recovery of normal kidney function. These data are
consistent with other retrospective series.53–57 Until more robust data are available
on the optimal administration and discontinuation of complement inhibitor therapy,
the decision to withdraw therapy should be made carefully.

Monitoring of complement activity is warranted during eculizumab therapy to ensure

its effectiveness. Of note, CH50 cannot be used for patients with complete CFH defi-
ciency because it is permanently low. The interval between doses can be extended if
adequate complement blockade is maintained. CH50 should be less than 10% for com-
plete blockade, but an activity less than 30% seems to be associated with sustained
disease remission despite reduced frequency of eculizumab administration.58
When eculizumab is not available, plasma exchange remains the preferred interven-
tion, and it should also be started promptly within 24 to 48 hours of diagnosis to
enhance efficacy.59 Liver transplant is an alternative curative intervention when dis-
ease is driven by a protein synthetized by the liver (FH, FB, C3, and FI).
Variants in Complement-Independent Genes

The variants of these genes, which are transmitted as autosomal recessive traits, do
not lead to overt complement dysfunction and therefore do not theoretically respond
to complement inhibitors.
cblC gene variants (cobalamin-C)

Renal thrombotic microangiopathy has been described as a complication of
cobalamin-C (cblC) deficiency due to cblC gene variants since the 1990s.60 These var-
iants underlie the combined methylmalonic aciduria (MMA) and homocystinuria, a
genetically heterogeneous disorder of cobalamin (cbl; vitamin B12) metabolism. The
majority of patients have an early onset in infancy, mostly within their first 4 months
and many in their first days of life.61 In addition to acute metabolic decompensations,
patients may display intrauterine growth retardation, congenital heart disease, visual
impairment, and nystagmus due to optic atrophy and retinopathy. They develop a pro-
gressive complex neurological phenotype with developmental delay, behavior pertur-
bances, and peripheral neuropathy. Fulminant, often lethal manifestations with early
onset aHUS and pulmonary hypertension have been reported, some with missed diag-
nosis or delayed treatment.62 The diagnosis should be suspected in the presence of
megaloblastosis. The specific treatment consisting of hydroxocobalamin and betaine
may prevent metabolic crises and improve kidney function including in dialysis-
dependent infants and should therefore be promptly initiated in all infants with unclear
aHUS while waiting for the results of blood/plasma homocysteine levels and/or ge-
netic testing of the MMACHC gene.61
DGKE gene variants (diacylglycerol kinase ε, 1%–17%)

Diacylglycerol kinase ε is an intracellular lipid kinase that phosphorylates diacylgly-
cerol to phosphatidic acid, resulting in protein kinase C activation. The exact mecha-
nism by which DGKE deficiency drives aHUS has not yet been unraveled. Such
variants were reported in infants (median age 9 months) affected with aHUS and a
particular phenotype characterized by persistent proteinuria, hematuria, and severe
hypertension with progressive chronic kidney disease.63,64 The kidney histology is
also characteristic with respect to glomerular cellularity, split glomerular basement
membranes, swelling of endothelial cells, and widening of the glomerular basement
membrane internal lamina rara in the absence of electron-dense deposition.63 Treat-
ment with eculizumab does not seem to result in long-term clinical improvement in
children with DGKE variants, and relapses have been described despite complement
blockade65; this suggests that complement inhibitors should be withheld in such
cases to avoid unwarranted side effects. Remarkably, no relapses have been pub-
lished in transplanted patients.

Atypical Hemolytic Uremic Syndrome with Anticomplement Autoantibodies

Autoantibodies directed against complement regulators (factor H, factor I) account for
approximately 6% to 25% of cases of aHUS with a pediatric onset.66,67
Anticomplement factor H autoantibodies

Anti-CFH IgGs are by far the most common autoantibodies identified in patients with
aHUS. These antibodies cause aHUS in 5% to 25% of patients in Europe but greater
than 50% of patients in South Asia.68 They bind to multiple factor H domains, thereby
perturbing its interaction with C3b and cell surfaces, ultimately reducing the ability of
factor H to prevent damage.69 More than 90% patients bear a homozygous deletion of
CFHR1 and CFHR3 genes.70 Of note, this deletion is also found in 2% to 5% of healthy
individuals in the general population. At the disease onset, the majority of patients
exhibit hallmarks of alternative complement pathway activation (decreased C3 and/
or factor B levels), and a subgroup of patients also have a decrease in factor H levels.27
Other autoantibodies such as antinuclear antibodies may be present in some patients.
CFH antibody–mediated aHUS typically manifest in school-aged children (7–
10 years). Most cases present with a full triad of HUS manifestations, and a prodromal
diarrhea has been reported in up to 80% cases, along with other infectious triggers in
some patients.27 Extrarenal complications are frequent and more than half of the pa-
tients require initial dialysis. Relapses are common and typically occur within the first 2
years after initial presentation, and the risk of kidney failure or death is higher in the
absence of adequate treatment. The risk of post-kidney transplant recurrence is high.
Besides symptomatic treatments, the specific management of CFH antibody–
mediated aHUS is challenging and evolving with the availability of complement inhib-
itors. The goals of treatment are to induce a rapid and sustained remission without dis-
ease recurrence. There is currently no consensus on the optimal regimen. The
classical approach consisted of plasma exchanges aiming to rapidly remove circu-
lating anti-CFH antibodies,71 followed by immunosuppressive therapy to reduce the
production of anti-CFH antibodies.2 Dragon-Durey and colleagues69 reviewed the
treatment efficacy in published series and showed a 17% to 29% risk of relapse
and 35% to 46% risk of chronic kidney disease stage 4 or 5 or death in case of sup-
portive care or plasmapheresis-based protocols as opposed to 10% and 14% if
plasma exchanges were combined to immunosuppressants.
Various combinations of immunosuppressants have been reported to be effective
and these include corticosteroids, intravenous cyclophosphamide, rituximab, and oral
mycophenolate mofetil.72 For instance, a combination of 2 to 4 plasma exchanges
and 2 mini-pulses of cyclophosphamide with a short trial of oral steroids has been
shown to allow sustained treatment-free remission for up to 15 years.42 At present,
following the aforementioned international recommendation, eculizumab is often started
before the identification of anti-CFH antibodies.2 Thus, when the diagnosis is confirmed,
2 approaches are possible: (1) switch eculizumab to start plasma exchanges and immu-
nosuppressants, especially if the child has a central line in place for dialysis, to reduce
the burden of long-term eculizumab therapy; (2) continue eculizumab in combination
with other immunosuppressants to avoid the possible complications of a central venous
line access.73 When antibody levels remain persistently low on immunosuppressants,
experts suggest to stop eculizumab with close monitoring before discontinuation of
other immunosuppressive drugs. Conversely, eculizumab alone without immunosup-
pression, although effective in controlling the disease and improving organ function,
does not decrease the anti-CFH antibody titer and must therefore be continued indef-
initely; otherwise there is a high risk of relapse.74 Future research should seek to clearly
define the optimal treatment of CFH antibody–mediated aHUS.

Anticomplement factor I autoantibodies

Recently, anti-CFI autoantibodies have been described in a few children who notably
had 2 copies of the CFHR1 and CFHR3 genes and low levels of factor H. They seem to
be more common in India and in children younger than 2 years, whereas children older
than 2 years have predominantly anti-CFH antibodies.75 Plasmapheresis carried out in
2 children resulted in a rapid improvement.
SUMMARY
HUS is due to a thrombotic microangiopathy affecting mainly the kidney. In children,

HUS is most often secondary to an infection from STEC. Risk factors for poor out-
comes include increased leukocyte count, the need for dialysis and its duration,
and the extent of glomerular involvement. Early volume expansion improves the short-
and long-term outcomes. During the past 10 years, complement dysregulation has
been identified as the main cause of atypical HUS, enabling breakthroughs in the diag-
nosis and the therapy with monoclonal anti-C5 antibodies.
CLINICS CARE POINTS
In STEC-HUS, early volume expansion can reduce the risk of complications.

To avoid cardiovascular and pulmonary complications, the packed red blood cells (RBC)
should be avoided unless hemoglobin level is <6 g/dL or hematocrit <18 percent.“
Platelet transfusion is reserved for patients with clinically significant bleeding or if an
invasive procedure is required.
There is no benefit in using antithrombotic or antifibrinolytic agents, plasma infusions,
tissue-type plasminogen activator, and oral Shiga toxin-binding agents
Plasma infusion and plasmapheresis should be avoided in pneumococcal- associated HUS
because it may aggravate hemolysis due to the presence of antibodies to the Thomsen-
Friedenreich antigen
Monoclonal complement inhibitor is the first-line treatment in patients with atypical-HUS.
A prompt plasma exchange is recommended if monoclonal complement inhibitor is not
available
REFERENCES
1. Fakhouri F, Zuber J, Fremeaux-Bacchi V, et al. Haemolytic uraemic syndrome.

Lancet 2017;390(10095):681–96.
2. Loirat C, Fakhouri F, Ariceta G, et al. An international consensus approach to the
management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol
(Berlin, Germany) 2016;31(1):15–39.
3. Gould LH, Mody RK, Ong KL, et al. Increased recognition of non-O157 Shiga
toxin-producing Escherichia coli infections in the United States during 2000-
2010: epidemiologic features and comparison with E. coli O157 infections. Food-
borne Pathog Dis 2013;10(5):453–60.
4. Kim JS, Lee MS, Kim JH. Recent Updates on Outbreaks of Shiga Toxin-Producing
Escherichia coli and Its Potential Reservoirs. Front Cell Infect Microbiol 2020;
10:273.
5. Vaillant V, Espie E, de Valk H, et al. Undercooked ground beef and person-to-
person transmission as major risk factors for sporadic hemolytic uremic

syndrome related to Shiga-toxin producing Escherchia coli infections in children

in France. Pediatr Infect Dis J 2009;28(7):650–3.
6. Psotka MA, Obata F, Kolling GL, et al. Shiga toxin 2 targets the murine renal col-
lecting duct epithelium. Infect Immun 2009;77(3):959–69.
7. Zoja C, Buelli S, Morigi M. Shiga toxin-associated hemolytic uremic syndrome:
pathophysiology of endothelial dysfunction. Pediatr Nephrol (Berlin, Germany)
2010;25(11):2231–40.
8. Khalid M, Andreoli S. Extrarenal manifestations of the hemolytic uremic syndrome
associated with Shiga toxin-producing Escherichia coli (STEC HUS). Pediatr
Nephrol (Berlin, Germany) 2019;34(12):2495–507.
9. Nathanson S, Kwon T, Elmaleh M, et al. Acute neurological involvement in
diarrhea-associated hemolytic uremic syndrome. Clin J Am Soc Nephrol 2010;
5(7):1218–28.
10. Brown CC, Garcia X, Bhakta RT, et al. Severe acute neurologic involvement in
children with hemolytic-uremic syndrome. Pediatrics 2021;147(3). e2020013631.
11. Percheron L, Gramada R, Tellier S, et al. Eculizumab treatment in severe pediatric
STEC-HUS: a multicenter retrospective study. Pediatr Nephrol (Berlin, Germany)
2018;33(8):650–3.
12. Lapeyraque AL, Malina M, Fremeaux-Bacchi V, et al. Complement blockade in
severe shiga-toxin-associated HUS. N Engl J Med 2011;364(26):2561–3.
13. Greinacher A, Friesecke S, Abel P, et al. Treatment of severe neurological deficits
with IgG depletion through immunoadsorption in patients with Escherichia coli
O104:H4-associated haemolytic uraemic syndrome: a prospective trial. Lancet
2011;378(9797):1166–73.
14. Grisaru S, Xie J, Samuel S, et al. Associations between hydration status, intrave-
nous fluid administration, and outcomes of patients infected with shiga toxin-
producing escherichia coli: a systematic review and meta-analysis. JAMA Pediatr
2017;171(1):68–76.
15. Bell BP, Griffin PM, Lozano P, et al. Predictors of hemolytic uremic syndrome in
children during a large outbreak of Escherichia coli O157:H7 infections. Pediat-
rics 1997;100(1):E12.
16. Wong CS, Jelacic S, Habeeb RL, et al. The risk of the hemolytic-uremic syndrome
after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med
2000;342(26):1930–6.
17. Ikeda K, Ida O, Kimoto K, et al. Effect of early fosfomycin treatment on prevention
of hemolytic uremic syndrome accompanying Escherichia coli O157:H7 infection.
Clin Nephrol 1999;52(6):357–62.
18. Copelovitch L, Kaplan BS. Streptococcus pneumoniae-associated hemolytic ure-
mic syndrome. Pediatr Nephrol (Berlin, Germany) 2008;23(11):1951–6.
19. Geary DF. Hemolytic uremic syndrome and streptococcus pneumoniae:
improving our understanding. J Pediatr 2007;151(2):113–4.
20. Scobell RR, Kaplan BS, Copelovitch L. New insights into the pathogenesis of
Streptococcus pneumoniae-associated hemolytic uremic syndrome. Pediatr
21. Spinale JM, Ruebner RL, Kaplan BS, et al. Update on Streptococcus pneumoniae
associated hemolytic uremic syndrome. Curr Opin Pediatr 2013;25(2):203–8.
22. Noris M, Remuzzi G. Genetics and genetic testing in hemolytic uremic syndrome/
thrombotic thrombocytopenic purpura. Semin Nephrol 2010;30(4):395–408.
23. 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(3):539–51.

24. Lemaire M, Noone D, Lapeyraque AL, et al. Inherited kidney complement dis-
eases. Clin J Am Soc Nephrol 2021;16(6):942–56.
25. Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J
Rare Dis 2011;6:60.
26. Fidan K, Goknar N, Gulhan B, et al. Extra-Renal manifestations of atypical hemo-
lytic uremic syndrome in children. Pediatr Nephrol (Berlin, Germany) 2018;33(8):
1395–403.
27. Dragon-Durey MA, Sethi SK, Bagga A, et al. Clinical features of anti-factor H
autoantibody-associated hemolytic uremic syndrome. J Am Soc Nephrol 2010;
21(12):2180–7.
28. Noris M, Brioschi S, Caprioli J, et al. Familial haemolytic uraemic syndrome and
an MCP mutation. Lancet 2003;362(9395):1542–7.
29. Ardissino G, Longhi S, Porcaro L, et al. Risk of Atypical HUS Among Family Mem-
bers of Patients Carrying Complement Regulatory Gene Abnormality. Kidney Int
Rep 2021;6(6):1614–21.
30. Kavanagh D, Goodship TH, Richards A. Atypical hemolytic uremic syndrome.
Semin Nephrol 2013;33(6):508–30.
31. Maga TK, Nishimura CJ, Weaver AE, et al. Mutations in alternative pathway com-
plement proteins in American patients with atypical hemolytic uremic syndrome.
Hum Mutat 2010;31(6):E1445–60.
32. Jokiranta TS, Jaakola VP, Lehtinen MJ, et al. Structure of complement factor H
carboxyl-terminus reveals molecular basis of atypical haemolytic uremic syn-
drome. EMBO J 2006;25(8):1784–94.
33. Lehtinen MJ, Rops AL, Isenman DE, et al. Mutations of factor H impair regulation
of surface-bound C3b by three mechanisms in atypical hemolytic uremic syn-
drome. J Biol Chem 2009;284(23):15650–8.
34. Pickering MC, Cook HT. Translational mini-review series on complement factor H:
renal diseases associated with complement factor H: novel insights from humans
and animals. Clin Exp Immunol 2008;151(2):210–30.
35. Fremeaux-Bacchi V, Fakhouri F, Garnier A, et al. Genetics and outcome of atyp-
ical hemolytic uremic syndrome: a nationwide French series comparing children
and adults. Clin J Am Soc Nephrol 2013;8(4):554–62.
36. Fang CJ, Fremeaux-Bacchi V, Liszewski MK, et al. Membrane cofactor protein
mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3
glomerulonephritis, and the HELLP syndrome. Blood 2008;111(2):624–32.
37. Klambt V, Gimpel C, Bald M, et al. Different approaches to long-term treatment of
aHUS due to MCP mutations: a multicenter analysis. Pediatr Nephrol (Berlin, Ger-
many) 2021;36(2):463–71.
38. Kavanagh D, Kemp EJ, Mayland E, et al. Mutations in complement factor I pre-
dispose to development of atypical hemolytic uremic syndrome. J Am Soc Neph-
rol 2005;16(7):2150–5.
39. Fremeaux-Bacchi V, Dragon-Durey MA, Blouin J, et al. Complement factor I: a
susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet
2004;41(6):e84.
40. Bienaime F, Dragon-Durey MA, Regnier CH, et al. Mutations in components of
complement influence the outcome of Factor I-associated atypical hemolytic ure-
mic syndrome. Kidney Int 2010;77(4):339–49.
41. 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(8):2392–400.

42. Zuber J, Fakhouri F, Roumenina LT, et al. Use of eculizumab for atypical haemo-
lytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol 2012;8(11):
643–57.
43. Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, et al. Gain-of-function mu-
tations in complement factor B are associated with atypical hemolytic uremic syn-
drome. Proc Natl Acad Sci United States America 2007;104(1):240–5.
44. Roumenina LT, Jablonski M, Hue C, et al. Hyperfunctional C3 convertase leads to
complement deposition on endothelial cells and contributes to atypical hemolytic
uremic syndrome. Blood 2009;114(13):2837–45.
45. Noris M, Caprioli J, Bresin E, et al. Relative role of genetic complement abnormal-
ities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J
Am Soc Nephrol 2010;5(10):1844–59.
46. Loirat C, Macher MA, Elmaleh-Berges M, et al. Non-atheromatous arterial steno-
ses in atypical haemolytic uraemic syndrome associated with complement dysre-
gulation. Nephrol Dial Transpl 2010;25(10):3421–5.
47. Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor eculizumab
in atypical hemolytic-uremic syndrome. N Engl J Med 2013;368(23):2169–81.
48. Licht C, Greenbaum LA, Muus P, et al. Efficacy and safety of eculizumab in atyp-
ical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kid-
ney Int 2015;87(5):1061–73.
49. 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(3):701–11.
50. 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
naive to complement inhibitor treatment. Kidney Int 2020;97(6):1287–96.
51. Macia M, de Alvaro Moreno F, Dutt T, et al. Current evidence on the discontinua-
tion of eculizumab in patients with atypical haemolytic uraemic syndrome. Clin
Kidney J 2017;10(3):310–9.
52. 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(18):2438–49.
53. 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 Kid-
ney Dis 2014;64(4):633–7.
54. Fakhouri F, Fila M, Provot F, et al. Pathogenic Variants in Complement Genes and
Risk of Atypical Hemolytic Uremic Syndrome Relapse after Eculizumab Discon-
tinuation. Clin J Am Soc Nephrol 2017;12(1):50–9.
55. Merrill SA, Brittingham ZD, Yuan X, et al. Eculizumab cessation in atypical hemo-
lytic uremic syndrome. Blood 2017;130(3):368–72.
56. Wijnsma KL, Duineveld C, Wetzels JFM, et al. Eculizumab in atypical hemolytic
uremic syndrome: strategies toward restrictive use. Pediatr Nephrol (Berlin, Ger-
many) 2019;34(11):2261–77.
57. Ariceta G. Optimal duration of treatment with eculizumab in atypical hemolytic
uremic syndrome (aHUS)-a question to be addressed in a scientific way. Pediatr
58. Ardissino G, Tel F, Sgarbanti M, et al. Complement functional tests for monitoring
eculizumab treatment in patients with atypical hemolytic uremic syndrome: an up-
date. Pediatr Nephrol (Berlin, Germany) 2018;33(3):457–61.

59. Bagga A, Khandelwal P, Mishra K, et al. Hemolytic uremic syndrome in a devel-

oping country: Consensus guidelines. Pediatr Nephrol (Berlin, Germany) 2019;
34(8):1465–82.
60. Geraghty MT, Perlman EJ, Martin LS, et al. Cobalamin C defect associated with
hemolytic-uremic syndrome. J Pediatr 1992;120(6):934–7.
61. Huemer M, Baumgartner MR. The clinical presentation of cobalamin-related dis-
orders: From acquired deficiencies to inborn errors of absorption and intracellular
pathways. J Inherit Metab Dis 2019;42(4):686–705.
62. Beck BB, van Spronsen F, Diepstra A, et al. Renal thrombotic microangiopathy in
patients with cblC defect: review of an under-recognized entity. Pediatr Nephrol
(Berlin, Germany) 2017;32(5):733–41.
63. Lemaire M, Fremeaux-Bacchi V, Schaefer F, et al. Recessive mutations in DGKE
cause atypical hemolytic-uremic syndrome. Nat Genet 2013;45(5):531–6.
64. Ozaltin F, Li B, Rauhauser A, et al. DGKE variants cause a glomerular microangi-
opathy that mimics membranoproliferative GN. J Am Soc Nephrol 2013;24(3):
377–84.
65. Brocklebank V, Kumar G, Howie AJ, et al. Long-term outcomes and response to
treatment in diacylglycerol kinase epsilon nephropathy. Kidney Int 2020;97(6):
1260–74.
66. Dragon-Durey MA, Loirat C, Cloarec S, et al. Anti-Factor H autoantibodies asso-
ciated with atypical hemolytic uremic syndrome. J Am Soc Nephrol 2005;16(2):
555–63.
67. Hofer J, Janecke AR, Zimmerhackl LB, et al. Complement factor H-related protein
1 deficiency and factor H antibodies in pediatric patients with atypical hemolytic
uremic syndrome. Clin J Am Soc Nephrol 2013;8(3):407–15.
68. Puraswani M, Khandelwal P, Saini H, et al. Clinical and immunological profile of
anti-factor H antibody associated atypical hemolytic uremic syndrome: a nation-
wide database. Front Immunol 2019;10:1282.
69. Durey MA, Sinha A, Togarsimalemath SK, et al. Anti-complement-factor H-asso-
ciated glomerulopathies. Nat Rev Nephrol 2016;12(9):563–78.
70. Dragon-Durey MA, Blanc C, Garnier A, et al. Anti-factor H autoantibody-
associated hemolytic uremic syndrome: review of literature of the autoimmune
form of HUS. Semin Thromb Hemost 2010;36(6):633–40.
71. Schwartz J, Winters JL, Padmanabhan A, et al. Guidelines on the use of thera-
peutic apheresis in clinical practice-evidence-based approach from the Writing
Committee of the American Society for Apheresis: the sixth special issue.
J Clin Apher 2013;28(3):145–284.
72. Sinha A, Gulati A, Saini S, et al. Prompt plasma exchanges and immunosuppres-
sive treatment improves the outcomes of anti-factor H autoantibody-associated
hemolytic uremic syndrome in children. Kidney Int 2014;85(5):1151–60.
73. Hackl A, Ehren R, Kirschfink M, et al. Successful discontinuation of eculizumab
under immunosuppressive therapy in DEAP-HUS. Pediatr Nephrol (Berlin, Ger-
many) 2017;32(6):1081–7.
74. Brocklebank V, Johnson S, Sheerin TP, et al. Factor H autoantibody is associated
with atypical hemolytic uremic syndrome in children in the United Kingdom and
Ireland. Kidney Int 2017;97(6):1260–74.
75. Govindarajan S, Rawat A, Ramachandran R, et al. Anti-complement factor I anti-
body associated atypical hemolytic uremic syndrome - A new insight for future
perspective! Immunobiology 2020;225(5):152000.


Hemolytic-Uremic Syndrome in Children

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Hemolytic-Uremic Syndrome in Children

Uploaded by

Copyright:

Available Formats

H e m o l y t i c - U re m i c S y n d ro m e

The hemolytic uremic syndrome (HUS), defined by the simultaneous occurrence of

Pediatr Clin N Am 69 (2022) 1181–1197

Descargado para Paula Andrea Murillo (pamurillotorres@gmail.com) en New Granada Military

INFECTION-INDUCED HEMOLYTIC UREMIC SYNDROME

Descargado para Paula Andrea Murillo (pamurillotorres@gmail.com) en New Granada Military

Fig. 2. Red blood cell fragmentation (schistocytes).

Descargado para Paula Andrea Murillo (pamurillotorres@gmail.com) en New Granada Military

Fig. 3. Thrombotic microangiopathy: “double contour” appearance of the capillary walls

Descargado para Paula Andrea Murillo (pamurillotorres@gmail.com) en New Granada Military

Fig. 4. Cortical necrosis.

Descargado para Paula Andrea Murillo (pamurillotorres@gmail.com) en New Granada Military

Pneumococcal-Associated Hemolytic Uremic Syndrome

Descargado para Paula Andrea Murillo (pamurillotorres@gmail.com) en New Granada Military

ATYPICAL HEMOLYTIC UREMIC SYNDROME

Atypical hemolytic uremic syndrome (aHUS) is a heterogeneous group of disorders

Fig. 6. Clinical presentation and evolution of STEC-HUS.

Descargado para Paula Andrea Murillo (pamurillotorres@gmail.com) en New Granada Military

vary depending on the underlying cause.25 Extrarenal manifestations of aHUS are

Complement Gene Variants

CFH gene variants (encoding complement factor H, reported mutation frequency

Descargado para Paula Andrea Murillo (pamurillotorres@gmail.com) en New Granada Military

CD46 gene variants (previously known as membrane cofactor protein, 5%–15%)

CFI gene variants (complement factor I, 5%–10%)

C3 gene variants (complement factor 3, 4%–7%)

CFB gene variants (complement factor B, 1%–2%)

THBD gene variants (thrombomodulin, 0%–5%)

Descargado para Paula Andrea Murillo (pamurillotorres@gmail.com) en New Granada Military

Descargado para Paula Andrea Murillo (pamurillotorres@gmail.com) en New Granada Military

Monitoring of complement activity is warranted during eculizumab therapy to ensure

Variants in Complement-Independent Genes

cblC gene variants (cobalamin-C)

DGKE gene variants (diacylglycerol kinase ε, 1%–17%)

Descargado para Paula Andrea Murillo (pamurillotorres@gmail.com) en New Granada Military

Atypical Hemolytic Uremic Syndrome with Anticomplement Autoantibodies

Anticomplement factor H autoantibodies

Descargado para Paula Andrea Murillo (pamurillotorres@gmail.com) en New Granada Military

Anticomplement factor I autoantibodies

HUS is due to a thrombotic microangiopathy affecting mainly the kidney. In children,

CLINICS CARE POINTS

 In STEC-HUS, early volume expansion can reduce the risk of complications.

1. Fakhouri F, Zuber J, Fremeaux-Bacchi V, et al. Haemolytic uraemic syndrome.

Descargado para Paula Andrea Murillo (pamurillotorres@gmail.com) en New Granada Military

syndrome related to Shiga-toxin producing Escherchia coli infections in children

Descargado para Paula Andrea Murillo (pamurillotorres@gmail.com) en New Granada Military

Descargado para Paula Andrea Murillo (pamurillotorres@gmail.com) en New Granada Military

Descargado para Paula Andrea Murillo (pamurillotorres@gmail.com) en New Granada Military

59. Bagga A, Khandelwal P, Mishra K, et al. Hemolytic uremic syndrome in a devel-

Descargado para Paula Andrea Murillo (pamurillotorres@gmail.com) en New Granada Military

You might also like

In STEC-HUS, early volume expansion can reduce the risk of complications.