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Hemolytic-Uremic Syndrome
Updated: Jun 06, 2024
Author: Malvinder S Parmar, MBBS, MS, FRCPC, FACP, FASN; Chief Editor: Srikanth Nagalla, MD, MS, FACP

Overview

Practice Essentials
Hemolytic-uremic syndrome (HUS) is a clinical syndrome characterized by progressive kidney failure that is associated with
microangiopathic (nonimmune, Coombs-negative) hemolytic anemia and thrombocytopenia.[1] HUS is the most common cause
of acute kidney injury in children and is increasingly recognized in adults.[2, 3, 4, 5]

Thrombotic thrombocytopenic purpura (TTP), childhood HUS, and adult HUS have different causes and demographics but share
many common features, especially in adults, which include similar pathologic changes such as microangiopathic hemolytic
anemia, thrombocytopenia, and neurologic or kidney abnormalities; see Presentation and Workup.

Initial therapy is similar for these conditions. Plasma exchange is the initial treatment of choice in all adult patients with HUS that
is not associated with Shiga-like toxin (atypical HUS). Two complement inhibitors, eculizumab and ravulizumab, are approved for
the treatment of pediatric and adult patients with atypical HUS. (See Treatment.)

See also Pediatric Hemolytic Uremic Syndrome.

Background
The Swiss pediatric hematologist Conrad von Gasser and colleagues first described hemolytic-uremic syndrome (HUS) in 1955.
[6] In 1983, Karmali and colleagues reported finding a toxin produced by specific strains of Escherichia coli in the stools of
children with HUS. This toxin was lethal to Vero cells (a line of kidney cells isolated from the African green monkey), and so was
termed verotoxin. Also in 1983, O’Brien and colleagues purified a lethal toxin from the enteropathogenic E coli O157:H7 strain
that structurally resembled that of Shigella dysenteriae type 1, and termed it Shiga-like toxin (both terms honor the Japanese
bacteriologist Kiyoshi Shiga, who in 1898 discovered S dysenteriae and its toxin as the cause of dysentery).[7, 8]

The term Shiga-like toxin was replaced with the term Shiga toxin when the two were found to be identical. E coli strains produce
two types of Shiga toxins. Shiga toxin type 1 (Stx1) is identical to the toxin produced by Shigella spp or differs by only one amino
acid. Stx2 is structurally and functionally similar to Stx1 but immunologically distinct; it shares approximately 50% homology with
Stx1 but the two are not cross-neutralized with heterologous antibodies. Stx2 is strongly associated with hemorrhagic colitis and
HUS. In addition, there are 10 subtypes of Stx1 and Stx2, each of which is divided into variants, which have
different pathogenicity. The capacity of certain E coli strains to produce Shiga toxins appears to have resulted from transduction
of the responsible genes by bacteriophages.[7, 8]

In 1988, Wardle described HUS and TTP as distinct entities, but in 1987, Remuzzi suggested that these two conditions are
varied expressions of the same entity. Confirmation that HUS and TTP are clearly different diseases, despite their clinical
similarities, followed the discovery of the von Willebrand factor (vWF)–cleaving metalloprotease ADAMTS13 (A disintegrin and
metalloprotease with a thrombospondin type 1 motif, member 13). Researchers subsequently recognized the etiologic link
between TTP and congenital deficiencies of ADAMTS13 or formation of acquired antibodies to ADAMTS13.[9, 10, 11, 12]

Pathophysiology
Damage to endothelial cells is the primary event in the pathogenesis of hemolytic-uremic syndrome (HUS). The cardinal lesion
is composed of arteriolar and capillary microthrombi (thrombotic microangiopathy [TMA]) and red blood cell (RBC)

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fragmentation.

HUS is classified into two main categories, depending on whether it is associated with Shiga toxin (Stx) or not.[13, 14]

Typical (Stx–associated) HUS

Typical HUS (Shiga toxin–associated HUS [Stx-HUS]) is the classic, primary or epidemic, form of HUS. Stx-HUS is largely a
disease of children younger than 2-3 years and often results in diarrhea (denoted D+HUS). One fourth of patients present
without diarrhea (denoted D-HUS). Acute kidney injury occurs in 55-70% of patients, but they have a favorable prognosis, and
as many as 70-85% of patients recover kidney function.

In Asia and Africa, typical HUS is often associated with Stx-producing Shigella dysenteriae serotype 1. In North America and
Western Europe, 70% of Stx-associated HUS cases are secondary to E coli serotype O157:H7. Other E coli serotypes
implicated include the following[15] :

O111:H8
O103:H2
O121
O145
O26
O113
O104:H4

After ingestion, Stx–E coli closely adheres to the epithelial cells of the gut mucosa by means of a 97-kd outer-membrane protein
(intimin). The route by which Stx is transported from the intestine to the kidney is debated. Some studies have highlighted the
role of polymorphonuclear neutrophils (PMNs) in the transfer of Stx in the blood, because Stx rapidly and completely binds to
PMNs when incubated with human blood. However, the receptor expressed on glomerular endothelial cells has 100-fold higher
affinity than of PMN receptors; in this way, they thereby transfer the Stx-ligand to glomerular endothelial cells.

The binding of Stx to target cells depends on B subunits and occurs by means of the terminal digalactose moiety of the
glycolipid cell-surface receptor globotriaosylceramide Gb3. Both Stx-1 and Stx-2 bind to different epitopes on the receptor with
different affinities. Stx-1 binds to and detaches easily from Gb3, whereas Stx-2 binds and dissociates slowly, causing more
severe disease than that due to Stx-1.

Data from some studies have suggested that Stx favors leukocyte-dependent inflammation by altering endothelial cell-adhesion
properties and metabolism, ultimately resulting in microvascular thrombosis. Findings from earlier studies suggested that
fibrinolysis is augmented in Stx-HUS, but results of more recent studies revealed higher-than-normal levels of plasminogen-
activator inhibitor type 1 (PAI-1), indicating that fibrinolysis is substantially inhibited.

Atypical (non–Stx-associated) HUS

Non–Stx-HUS, or atypical HUS, is less common than Stx-HUS and accounts for 5-10% of all cases. As the name indicates,
non–Stx-HUS does not result from infection by Stx-producing bacteria. Unlike HUS caused by enterohemorrhagic E coli, which
occurs principally in summer, atypical HUS may occur year-round without a gastrointestinal prodrome (D- HUS). Atypical HUS is
a complement-mediated thrombotic microangiopathy.

Non–Stx-HUS may occur at all ages but is most frequent in adults and occurs without prodromal diarrhea (D- HUS). It can occur
in sporadic cases or in families. The familial form is associated with genetic abnormalities of the complement regulatory proteins.

Overall, patients with non–Stx-HUS have a poor outcome, with as many as 50% progressing to end-stage renal disease (ESRD)
or irreversible brain damage. Up to 25% of patients die during the acute phase.

Sporadic non–Stx-associated HUS

Various triggers for sporadic non-Stx–HUS have been identified, including the following:

Nonenteric infections
Viruses
Drugs
Malignancies
Transplantation
Pregnancy [16]
In rare cases, other underlying medical conditions (eg, antiphospholipid syndrome [APL], systemic lupus erythematosus
[SLE])

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Streptococcus pneumoniae infection accounts for 40% of all causes of non-Stx–HUS and 4.7% of all causes of HUS in children
in the United States. The pathogenesis in these cases appears to have several mechanisms. For example, S
pneumoniae strains isolated from patients with pneumococcal-induced HUS have been shown to bind high levels of human
plasminogen, which when activated to yield plasmin causes damage to endothelial cells, with exposure of the underlying matrix;
this leads to thrombosis.[17, 18] Clinically, pneumococcal-induced HUS is usually severe, with respiratory distress, neurologic
involvement, and coma, with a mortality rate of up to 50%.

Familial non–Stx-associated HUS

Familial non–Stx-HUS accounts for less than 3% of all cases of HUS. Both autosomal dominant and autosomal recessive forms
of inheritance are observed. Autosomal recessive HUS often occurs early in childhood. The prognosis is poor, recurrences are
frequent, and the mortality rate is 60-70%. Autosomal dominant HUS often occurs in adults, who also have a poor prognosis,
with a 50-90% risk of death or ESRD.

Data suggest that familial non–Stx-HUS results from genetic abnormalities in the complement regulatory proteins, including C3,
factor H, factor B, factor I, and CD46 (membrane cofactor protein, MCP). Factor H appears to be particularly important.[19, 20,
21, 22]

Factor H (HF1) consists of 20 homologous units called short consensus repeats (CSRs) and plays an important role in the
regulation of the alternative pathway of complement. HF1 also serves as a cofactor for the C3b-cleaving enzyme factor I in the
degradation of newly formed C3b molecules. It controls the decay, formation, and stability of C3b convertase (C3bBb), and it
protects glomerular endothelial cells and the basement membrane against complement attack by binding to the polyanionic
proteoglycans on the surface of endothelial cells and in the subendothelial matrix.

Fifty HF1 mutations have been described in 80 patients who had familial (36 patients) and sporadic (44 patients) forms of non–
Stx-HUS. The mutation frequency is 40% in the familial form and 13-17% in the sporadic form. One patient with Stx-HUS who
did not recover kidney function was noted to have a mutation in exon 23 of the factor H gene.[21]

Patients with HF1 mutations have partial HF1 deficiency that causes a predisposition to the disease rather than the disease
itself. Mutant HF1 has normal cofactor activity in the fluid phase, but its binding to proteoglycans is reduced, because the
mutation affects the polyanion interaction at the C-terminus of HF1. Suboptimal HF1 activity is often enough to protect the
patient from complement activation in physiologic conditions. However, activation of complement pathways results in higher-
than-normal concentration of C3b, and its deposition on vascular endothelial cells cannot be prevented because of the inability
of mutant HF1 to bind to polyanion proteoglycans.

Etiology
Hemolytic-uremic syndrome (HUS) predominantly occurs in infants and children after prodromal diarrhea. In summer epidemics,
the disease may be related to infectious causes.

Bacterial infections may include the following:

Shigella dysenteriae
E coli
Salmonella typhi
Campylobacter jejuni
Yersinia pseudotuberculosis
Neisseria meningitidis
Streptococcus pneumoniae
Legionella pneumophila
Mycoplasma species

Viral infections may include the following:

Human immunodeficiency virus (HIV)

Coxsackievirus
Echovirus
Influenza virus
Epstein-Barr virus
Herpes simplex virus
Norovirus [23]

Fungal infections can include Aspergillus fumigatus.

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Vaccinations may include the following:

Influenza triple-antigen vaccine

Typhoid-paratyphoid A and B (TAB) vaccine
Polio vaccine
mRNA-based COVID-19 vaccine [24]

Causes of the secondary or sporadic form may include the following:

Pregnancy and puerperium

Cancers (chiefly mucin-producing adenocarcinomas)
Drugs
Malignant hypertension
Collagen-vascular disorder (eg, systemic lupus erythematosus [SLE], antiphospholipid antibody syndrome) - It is possible
to have both true HUS and a lupus anticoagulant, but in most patients, the thrombocytopenia, microangiopathic
hemolytic, and kidney disease are due to antiphospholipid antibodies rather than true HUS
Primary glomerulopathies
Transplantation (eg, of kidney, bone marrow): This can be de novo or recurrent. It occurs in 5-15% of kidney transplant
patients who receive cyclosporine and in about 1% of patients who receive tacrolimus.
Allogeneic hematopoietic stem cell transplantation (HSCT)

Pregnancy-associated HUS occasionally develops as a complication of preeclampsia. Patients may progress to full-blown
hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Postpartum HUS usually occurs within 3 months of
delivery. The prognosis is poor, with a 50-60% mortality rate, and residual kidney dysfunction and hypertension occur in most
patients.

Drugs implicated in causing non–Stx-HUS are as follows:

Quinine - Most common cause of drug-induced TTP-HUS and has been confirmed to cause recurrent disease with
recurrent exposure; chronic kidney disease appears to be common following quinine-induced HUS[25]

Anticancer agents: These include mitomycin, cisplatin, bleomycin, and gemcitabine. The risk for HUS after mitomycin
therapy is 2-10%, and onset may be delayed, occurring almost 1 year after the patient starts treatment. The prognosis is
poor, with a 75% mortality rate at 4 months.

Immunotherapeutic agents: Examples are cyclosporine, tacrolimus, OKT3, and interferon.

Antiplatelet agents: Examples are ticlopidine and clopidogrel.

Oral contraceptives

Posttransplantation HUS is reported with increasing frequency and may be primary (de novo) or recurrent. It is often a
consequence of the use of calcineurin inhibitors or of humoral (C4b positive) rejection. This condition occurs in 5-15% of kidney
transplant patients treated with cyclosporine and in about 1% of patients treated with tacrolimus.

An immunodeficiency-related cause includes thymic dysplasia.

Familial causes account for 3% of all cases of HUS, and both autosomal dominant and autosomal recessive forms of inheritance
have been reported. Autosomal recessive HUS occurs in childhood, and patients have a poor prognosis with frequent
recurrences and a mortality rate of 60-70%. Autosomal dominant HUS occurs mostly in adults, who have a poor prognosis; the
cumulative incidence of death or ESRD is 50-90%.

No cause is identified in about 50% of all cases of sporadic non–Stx HUS.

Epidemiology
United States

Stx-HUS occurs with a frequency of 0.5-2.1 cases per 100,000 population per year, with a peak incidence in children younger
than 5 years, in whom the incidence is 6.1 cases per 100,000 population per year. In 2015, 274 cases of HUS were reported in
the United States, 122 of them in children 1-4 years of age.[26]

Non–Stx-HUS accounts for 5-10% of all cases of HUS, and the incidence in children is about one-tenth of that of Stx-HUS. This
rate corresponds to about 2 cases per 100,000 population per year.

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International

In children younger than 15 years, typical HUS occurs at a rate of 0.91 cases per 100,000 population in Great Britain, 1.25
cases per 100,000 population in Scotland, and 1.44 cases per 100,000 population in Canada.

Seasonal variation occurs, with cases peaking in the summer and fall.

Race-, Sex-, and Age-related Demographics

HUS occurs infrequently in blacks. Both sexes are affected equally with HUS.

HUS occurs mainly in young children; however, adolescents and adults are not exempt. In young children, spontaneous
recovery is common. In adults, the probability of recovery is low when HUS is associated with severe hypertension.

Mortality/Morbidity
For Stx-HUS, acute rkidney injury occurs in 55-70% of patients; up to 70-85% recover kidney function.

For non–Stx-HUS, patients have poor outcomes, with up to 50% progressing to ESRD or irreversible brain damage. As many as
25% die during the acute phase.

Complications of HUS may include the following:

Kidney failure
Stroke
Coma
Seizures
Bleeding

Schuppner et al reported that in an outbreak of Stx-associated HUS resulting from E coli O104:H4 infections in Germany in
2011, neurological complications occurred in 48-100% of adults in different patient groups. On follow-up conducted 19 months
after disease onset in 31 patients, 22 still suffered from symptoms such as fatigue, headache, and attention deficits. On
neuropsychological assessment, 61% of patients scored borderline pathological or lower. Secondary decline of cognitive
function was found in about one-quarter of the patients.[27]

Prognosis
Stx-HUS prognosis is as follows:

Acute kidney injury occurs in 55-70% of patients, but 85% recover kdiney function with supportive therapy.

Approximately 15-20% of children may develop hypertension 3-5 years after the onset of disease.

Recurrence with kidney allografting is 10% or lower.

A study by Balestracci et al comparing 145 cases of non-severe Stx-HUS with 71 severe cases found that a shorter prodromal
phase is associated with worse prognosis. Rates of severe disease were 75.8% in patients with a prodrome of 1-2 days, 29.6%
in those with a prodrome of 3-7 days, and 11.4% in those with a prodrome of 8 days or longer.[28]

Ardissino et al developed an early prognostic index for Stx-HUS outcome that uses the combination of hemoglobin (Hb) and
serum creatinine (sCr) concentrations at onset of illness. The formula is as follows:

Hb (in g/dL) + (sCr [in mg/dL] × 2)

On testing of the index in a cohort of of 197 Stx-HUS patients, 8% of those with a score > 13 died or entered a permanent
vegetative state, compared with 0% of those with a score of ≤ 13.[29]

Alconcher et al reported that the best independent predictors of mortality in children with Stx-HUS were central nervous system
(CNS) involvement, hyponatremia (serum sodium ≤ 128 meq/L) and elevated hemoglobin concentration (≥ 10.8 g/dL).[30]

Non–Stx-HUS prognosis is as follows:

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Patients collectively have a poor prognosis, and as many as 50-60% progress to ESRD (50% in those with the sporadic
forms and 60% in those with the familial forms) or develop irreversible brain damage. About 25% die during the acute
phase.

The recurrence rate in patients receiving kidney transplants is as high as 50%, with graft loss occurring in more than 90%
who have recurrence. Recurrence rates are higher in patients with HF1 mutation.

Factors predictive of poor prognosis are as follows:

Non–Stx-HUS
Prolonged oliguria or anuria
Severe hypertension (especially delayed onset of hypertension)
Involvement of medium-sized arteries
Severity of CNS symptoms
Persistent consumption of clotting factors
Extensive glomerular involvement (>80%)
Age older than 5 years

In a retrospective study of 323 adult kidney transplant recipients with HUS and 121,311 transplant recipients with other kidney
diseases, Santos and colleagues found that while mortality did not significantly differ between groups in the 5 years following
transplantation, death-censored graft loss occurred twice as often (hazard ratio 2.05) in patients whose native kidney disease
was HUS than in other transplant recipients. HUS patients with post-transplant recurrence had a 5-year graft loss rate
significantly higher than that of patients without recurrence (graft survival 14.7% vs 77.4%, P< 0.001).[31]

Patient Education
Advise patients to avoid eating raw or partially cooked meat. Improperly cooked or contaminated meat is a potential source of E
coli O157:H7. Educate patients on the proper treatment of drinking water. Communities must make adequate efforts to ensure
proper treatment and monitoring of drinking water. Educate patients about proper hygienic measures, especially in cattle fields
and farms.

For patient education information, see Blood in the Urine, and Acute Kidney Failure.

Presentation

History
The history in a patient with typical hemolytic-uremic syndrome (HUS) may include the following:

Prodromal gastroenteritis (83%) - Fever (56%), bloody diarrhea (50%) for 2-7 days
Irritability, lethargy
Seizures (20%)
Acute kidney injury (97%)
Anuria (55%)

Physical Examination
Physical findings may include the following:

Hypertension (47%)
Edema, fluid overload (69%)
Pallor, often severe

DDx
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Diagnostic Considerations
Other problems to consider include the following:

Decreased platelet count

Decreased plasma levels of clotting factors V and factor VIII
Increased activated partial thromboplastin time (aPTT) and prothrombin time (PT)
Increased D-dimer and fibrinogen-degradation products (FDP)Scleroderma renal crisis
Thrombotic microangiopathy in patients with cancer
Glucose-6-phosphate dehydrogenase (G6PD) deficiency [32]

Differential Diagnoses
Disseminated Intravascular Coagulation (DIC)

Malignant Hypertension

Pediatric Antiphospholipid Antibody Syndrome

Preeclampsia

Thrombotic Thrombocytopenic Purpura (TTP)

Workup

Workup

Approach Considerations
Hemolytic-uremic syndrome (HUS) is primarily a clinical diagnosis, confirmed by laboratory studies showing a microangiopathic
hemolytic anemia.

Biopsy findings pathologically establish the diagnosis of HUS. However, kidney biopsy is not required in children. In adults,
kidney biopsy is rarely required.

Perform kidney ultrasonography in patients with acute kidney injury, to rule out obstruction.

In patients with atypical hemolytic-uremic syndrome (aHUS), Kidney Disease: Improving Global Outcomes (KDIGO)
recommends genetic testing to identify an underllying hereditary abnormality.[33]

Laboratory Studies
Laboratory findings in patients with hemolytic-uremic syndrome (HUS) may include the following:

Urinalysis: Benign mild proteinuria is frequently present; red blood cells (RBCs) and RBC casts may be present

Measurement of blood urea nitrogen (BUN), serum creatinine, and serum electrolyte levels reveals acute kidney injury

Hematologic studies: Severe anemia may be present. On a peripheral smear, a schistocyte count > 1% or the presence
of two or more schistocytes in a 100× magnification field strongly suggests microangiopathic hemolysis.[34] Platelet
counts are typically decreased, but the degree of thrombocytopenia does not correlate with the severity or the length of
illness in HUS. The platelet count usually returns to normal within 2 weeks. Determine activated partial thromboplastin
time (aPTT), fibrinogen degradation product (FDP), and D-dimer values.

Hemolytic workup: Results may show anemia. Bilirubin levels may be elevated. Lactate dehydrogenase (LDH) levels may
be elevated. Haptoglobin levels may be decreased.

Stool culture: Obtain a sample for stool culture. Evaluate especially for E coli 0157:H7 and Shigella bacteria.

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ADAMTS-13 activity: ADAMTS-13 activity is often severely deficient (< 10% of normal) in patients with classic
thrombotic thrombocytopenic purpura (TTP), but this can also be seen in patients with severe sepsis (especially in
association with disseminated intravascular coagulation or multiorgan failure) and in patients with severe liver disease.

On complement serology testing, a decrease in both complement factor B (CFB) and CH50 may offer important support
for the diagnosis of atypical HUS.[35] In diarrhea-associated HUS, a lowered concentration of C3 (< 0.825 g/L) at the
time of initial presentation is associated with a more severe clinical course.[36]

Histologic Findings
The characteristic pathologic findings of hemolytic-uremic syndrome (HUS) are occlusive lesions of the arterioles and small
arteries and consequent tissue microinfarctions. In HUS, the lesions are usually limited to the kidneys, whereas the lesions are
more widespread in thrombotic thrombocytopenic purpura (TTP). Renal lesions are primarily focal and involve both the
glomerular capillaries and the afferent arterioles. The venous side of the circulation is usually spared.

A fully developed vascular lesion consists of amorphous-appearing, hyalinelike, thrombi-containing platelet aggregates and a
small amount of fibrin that partially or fully occludes the involved small vessels (see images below). Despite extensive arterial
changes, no perivascular cellular infiltration or evidence of associated vasculitis is present. Subendothelial deposits with
overlying endothelial proliferation may be present.

Photomicrograph (hematoxylin and eosin, original magnification ×25) shows diffuse thickening of the glomerular capillary wall
with double contouring (arrow) and swelling of endothelial cells. Fibrin thrombi and packed red blood cells are visible in the
lumina (arrowhead). Courtesy of Madeleine Moussa, MD, FRCPC, Department of Pathology, London Health Sciences Centre,
London, Ontario, Canada.

Photomicrograph (periodic acid-Schiff, original magnification ×40) shows diffuse thickening of the glomerular capillary wall
with double contouring (arrow) and swelling of endothelial cells. Courtesy of Madeleine Moussa, MD, FRCPC, Department of
Pathology, London Health Sciences Centre, London, Ontario, Canada.

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As a rule, changes in kidney function and the course of kidney failure correlate well with the pathologic findings in the kidney.
Obliterative arteriolar lesions are correlated with hypertension and progressive loss of kidney function. Glomerular thrombotic
microangiopathic lesions and cortical necrosis are the most frequent histologic findings in Stx-HUS, whereas arterial thrombotic
microangiopathic lesions are the most frequent features in non–Stx HUS.

Treatment

Medical Care
Specific treatments for Shiga toxin–associated hemolytic-uremic syndrome (Stx-HUS) have not proven of value. Instead,
comprehensive supportive therapy is still the mainstay during the acute phase.

There is no clear consensus on the use of antibiotics. The evidence suggests avoidance of antibiotics unless patient is septic.
An in-vitro study demonstrated that although growth-inhibitory levels of antibiotics suppressed Stx production, subinhibitory
levels of certain antibiotics that target DNA synthesis, including ciprofloxacin and trimethoprim-sulfamethoxazole, increased Stx
production.[37] Stx production did not increase with use of antibiotics that target the cell wall, transcription, or translation. In
contrast, Stx levels were significantly reduced with azithromycin, even when Escherichia coli O157:H7 viability remained high.

Kidney transplantation is safe and effective for children who progress to end-stage renal disease (ESRD). The recurrence rate in
patients who undergo kidney transplantation for HUS is 0-10%.

The US Food and Drug Administration (FDA) has approved two complement inhibitors for the treatment of atypical HUS:
eculizumab and ravulizumab. These monoclonal antibodies inhibit complement-mediated thrombotic microangiopathy. Both of
these agents carry black box warnings regarding meningococcal infection, which include a recommendation to immunize
patients with meningococcal vaccines at least 2 weeks before starting treatment.

Other treatments during the acute phase of the disease, including plasma therapy and use of intravenously infused
immunoglobulin (IgG), fibrinolytic agents, antiplatelet agents, corticosteroids, and antioxidants have proved ineffective in
controlled clinical trials.[38] Plasma exchange is not recommended as initial therapy in typical HUS.

Non–Styx-associated HUS

Plasma exchange is the initial treatment of choice in all adult patients with non-Stx–HUS (atypical HUS) or thrombotic
thrombocytopenic purpura (TTP) and should be considered as early as possible in the disease course. The remarkable decline
in mortality with the use of therapeutic plasma exchange has changed the course of this disease from fatal to mostly curable. At
present, the findings of unexplained thrombocytopenia and microangiopathic hemolytic anemia are sufficient to consider
thrombotic microangiopathy and initiate plasma exchange.

Plasma exchange might be more effective than infusion, as it removes potentially toxic substances from the circulation. Plasma
exchange rather than infusion should be considered first-line therapy in situations that limit the amount of plasma that can be
infused, such as renal impairment or heart failure.

Plasma treatment should be started within 24 hours of the patient's presentation, to decrease treatment failures. It should be
continued once or twice a day for at least 2 days after complete remission.

Plasma therapy is contraindicated in Streptococcus pneumoniae–induced non–Stx-HUS; it may exacerbate the disease because
adult plasma contains antibodies against the Thomsen-Friedenreich antigen. A case report describes efficacy of long-term, high-
dose plasma infusion (30 mL/kg) at weekly intervals over 30 months, but the long-term effects are still unknown.[22]

Eculizumab

Eculizumab (Soliris) was approved for the treatment of non–Stx-HUS (atypical HUS) by the FDA in 2011. Eculizumab is a
humanized monoclonal antibody against C5 that inhibits the activation of terminal components of complement.

The safety and effectiveness of eculizumab in non–Stx-HUS were established in two single-arm trials in 37 adults and
adolescents and one retrospective study in 19 pediatric and 11 adult patients. In those studies, eculizumab treatment led to
improvement in kidney function, including elimination of the need for dialysis in several cases that had not responded plasma
therapy. Patients treated with eculizumab also exhibited improvement in platelet counts and other blood parameters.[39]

Prospective phase II trials by Legendre and colleagues in 37 patients with non–Stx-HUS who were 12 years of age or older
demonstrated that a shorter interval between the clinical manifestation of the disease and the initiation of treatment) was
associated with significantly greater improvement in the estimated glomerular filtration rate. Legendre and colleagues concluded

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that, “the data highlight the inadequate efficacy of management with plasma exchange or infusion and confirm the clinically
relevant treatment effect of eculizumab.”[40]

In a prospective phase III trial by this group in 41 patients with non–Stx-HUS who were 18 years of age or older, 30 patients had
complete response of thrombotic microangiopathy, with normalization of the platelet count and lactate dehydrogenase (LDH)
level and, and preservation of kidney function. Other benefits included improved quality of life, discontinuation of dialysis, and
transplant protection.[41]

In the first prospective trial of eculizumab in pediatric non–Stx-HUS, Greenbaum et al reported that of 22 patients (5 months–17
years of age) 14 achieved a complete thrombotic microangiopathy response, 18 achieved hematologic normalization, and 16
had 25% or better improvement in serum creatinine. All patients were able to discontinue plasma exchange/infusion, and 9 of
the 11 patients who required dialysis at baseline discontinued; none initiated new dialysis. Eculizumab was well tolerated; no
deaths or meningococcal infections occurred.[42]

In a prospective study of eculizumab discontinuation after a mean treatment duration of 16.5 months in 36 adults and 19 children
with atypical HUS, Fakhouri et al reported an increased risk of relapse in female patients and those with a rare variant in a
complement gene (mostly in MCP, CFH, and CFI). An increased sC5b-9 plasma level at eculizumab discontinuation was also
associated with a higher risk of relapse However, requirement for dialysis during a previous episode of acute atypical HUS was
not associated with increased relapse risk. Of the patients who experienced relapse, 11 regained their baseline kidney function
after restarting eculizumab and 2 had a worsening of their preexisting chronic kidney disease, including 1 patient who
progressed to end-stage kidney disease.[43]

Ravulizumab

Ravulizumab (Ultomiris) was approved by the FDA in 2019 for the treatment of aHUS in adult and pediatric patients aged 1
month and older. Like eculizumab, ravlizumab is a monoclonal antibody that inhibits complement-mediated thrombotic
microangiopathy (TMA).

Approved was based on data from 2 ongoing single-arm open-label studies that evaluated the efficacy of ravulizumab
in pediatric (n=13) and adult (n=56) patients with aHUS. The studies demonstrated a complete TMA response in 71% of children
and 54% of adults during the initial 26-week treatment period, as evidenced by normalization of hematological parameters
(platelet count and LDH level) and ≥25% improvement in serum creatinine from baseline. Additionally, ravulizumab treatment
resulted in reduced thrombocytopenia in 93% of children and 84% of adults; reduced hemolysis in 86% of children and 77% of
adults; and improved kidney function in 79% of children and 59% of adults.[44]

Transplantation

In the past, kidney transplantation was not an option for patients with non–Stx-HUS (atypical HUS [aHUS]) because of the 50%
recurrence rate and > 90% rate of graft failure in patients with recurrence. Recurrence rates (30-100%) were significantly higher
in patients with HF1 mutations than in those without this mutation. In patients with MCP mutation, however, outcomes are
favorable; kidney transplantation may correct the local MCP dysfunction, as MCP is a membrane-bound protein that is highly
expressed in the kidney.

The advent of eculizumab broadened the indications for kidney transplantation in aHUS. Prophylactic eculizumab therapy—
initiated at transplantation, because most posttransplant recurrence of non–Stx-HUS occurs within the first year—has been used
to prevent recurrence and associated graft injury. In a United Kingdom study of 118 kidney transplants in 86 recipients who had
a confirmed diagnosis of aHUS, prophylactic eculizumab treatment improved allograft survival in medium and high-risk
recipients, with 1-y survival of 97% versus 64% in untreated patients.[45]

In the Netherlands, where kidney transplantation in patients with aHUS has been performed without eculizumab prophylaxis
since 2016, rescue treatment with eculizumab has proved effective. Some patients with recurrence have suffered irreversible
loss of kidney function, likely caused by delayed diagnosis and treatment and/or overly aggressive discontinuation of
eculizumab.[46]

In patients with HF1 genetic defect, liver transplantation was thought to correct the defect, because HF1 is a plasma protein of
hepatic origin. Combined liver and kidney transplantation has been used in HUS patients with mutations in Factor H, most of
them children. Initial attempts had a fatal outcome, but the introduction of pre-emptive plasmapheresis with plasma exchange
has proved very successful in improving results, although risks remain.[47]

Supportive therapy

Supportive therapy is as follows:

Maintain fluid and electrolyte balance

Adequate blood pressure control and adequate renin-angiotensin blockade, for patients who have chronic kidney disease
after an episode of Stx-HUS
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For seizure control, consider prophylactic phenytoin in patients with neurologic symptoms (20-40% of patients have
seizures)

Control azotemia

Optimize nutrition

Consultations
Patients with hemolytic-uremic syndrome (HUS) may require consultation with the following specialists:

Nephrologist
Hematologist
Neurologist in cases of neurologic involvement
Intensivists for intensive care unit (ICU) management

Diet
Provide nutritional support during the acute illness. If patients have severe diarrhea, they may require parenteral nutrition. Some
children with gastrointestinal involvement may require prolonged parenteral feeding. Early restriction of proteins, in addition to
renin-angiotensin blockade, may have a beneficial effect on the long-term renal outcome in patients who develop chronic kidney
disease after Stx-HUS.

Prevention
Because typical HUS commonly occurs in epidemics, consider this possibility and inform health authorities to monitor for the
possibility of index cases and to prevent the spread of disease in the community.

At present, prevention is the main approach to decreasing the morbidity and mortality associated with Stx–E coli infection.

Antibiotic treatment of children with E coli O157:H7 infection increases the risk of HUS and should be avoided unless they have
septicemia.[48]

Long-Term Monitoring
Although most pediatric patients with Stx-HUS recover completely, sequelae can develop years after the acute phase, so regular
long-term follow-up is needed. In a European study of 138 patients with Stx-HUS, 34% later presented with a decreased
glomerular filtration rate, proteinuria, hypertension, or neurologic symptoms. In most cases, onset of those sequelae occurred in
the first year after Stx-HUS, but in others the onset was delayed for as long as 10 years. Late onset of sequelae occurred more
commonly in patients who had experience critical illness in the acute phase, as indicated by need for kidney replacement
therapy or plasma treatment.[49]

Monitor kidney function and blood pressure, because as many as 80% of adults with HUS require long-term dialysis or kidney
transplantation.

Ensure adequate blood pressure control and consider renin-angiotensin blockade with angiotensin-converting enzyme inhibitors
(ACEIs) or angiotensin-receptor blockers.

Early protein restriction may be needed in patients who develop residual chronic kidney disease after the acute phase.

Medication

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Medication Summary
The US Food and Drug Administration has approved complement inhibitors for the treatment of hemolytic-uremic syndrome
(HUS) that is not associated with Shiva toxin (non–Stx-HUS; atypical HUS): eculizumab and ravulizumab.

Supportive care only is used for Stx-HUS (typical HUS). Medications for supportive care may include angiotensin-converting
enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) for control of hypertension, or phenytoin for prevention of
seizures.

Complement Inhibitors

Class Summary
Agents in this category may block the formation of membrane attack complex, which can stabilize the hemoglobin and reduce
the need for RBC transfusions.

Eculizumab (Soliris, Bkemv)

Monoclonal blocking antibody to complement protein C5; inhibits cleavage to C5a and C5b, thus preventing terminal
complement complex C5b-9, thereby preventing RBC hemolysis

Inhibits terminal complement mediated intravascular hemolysis in paroxysmal nocturnal hemoglobinuria and complement-
mediated thrombotic microangiopathy (TMA) in atypical hemolytic uremia synrome (aHUS)

Ravulizumab (Ultomiris)
Ravulizumab is a monoclonal blocking antibody to complement protein C5; it inhibits cleavage to C5a and C5b, thus preventing
terminal complement complex C5b-9, thereby preventing RBC hemolysis. It inhibits terminal complement-mediated intravascular
hemolysis in patients with paroxysmal nocturnal hemoglobinuria and complement-mediated thrombotic microangiopathy in
patients with aHUS.

Questions & Answers

Overview

What is hemolytic-uremic syndrome (HUS)?

When was hemolytic-uremic syndrome (HUS) first described?

What is the pathogenesis of atypical (non-Stx-associated) hemolytic-uremic syndrome (HUS)?

What is the pathogenesis of familial non-Stx-associated hemolytic-uremic syndrome (HUS)?

What is the primary event in the pathogenesis of hemolytic-uremic syndrome (HUS)?

How is hemolytic-uremic syndrome (HUS) categorized?

What is the pathogenesis of typical (Stx-associated) hemolytic-uremic syndrome (HUS)?

What are triggers for sporadic non-Stx-associated hemolytic-uremic syndrome (HUS)?

Which patient group is at highest risk for hemolytic-uremic syndrome (HUS)?

Which bacterial infections cause hemolytic-uremic syndrome (HUS)?

Which viral infections cause hemolytic-uremic syndrome (HUS)?

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Which fungal infection causes hemolytic-uremic syndrome (HUS)?

Which vaccines may cause hemolytic-uremic syndrome (HUS)?

What causes secondary or sporadic hemolytic-uremic syndrome (HUS)?

How does pregnancy-associated hemolytic-uremic syndrome (HUS) develop?

Which drugs are implicated in the etiology of non-Stx-hemolytic-uremic syndrome (HUS)?

What is the prevalence of hemolytic-uremic syndrome (HUS) following transplantation?

How prevalent is hemolytic-uremic syndrome (HUS) in the US?

How prevalent is hemolytic-uremic syndrome (HUS) globally?

How prevalent is hemolytic-uremic syndrome (HUS) by race and sex?

How prevalent is hemolytic-uremic syndrome (HUS) by age?

What are possible complications of hemolytic-uremic syndrome (HUS)?

What is the prevalence of neurological complications of hemolytic-uremic syndrome (HUS)?

What is the prognosis of Stx-hemolytic-uremic syndrome (HUS)?

What is the prognosis of non Stx-hemolytic-uremic syndrome (HUS)?

Which factors predict a poor prognosis for hemolytic-uremic syndrome (HUS)?

How does kidney transplant affect the prognosis of hemolytic-uremic syndrome (HUS)?

What information should be given to patients with hemolytic-uremic syndrome (HUS)?

Presentation

What are the signs and symptoms of hemolytic-uremic syndrome (HUS)?

Which physical findings suggest hemolytic-uremic syndrome (HUS)?

DDX

Which conditions should be included in the differential diagnoses of hemolytic-uremic syndrome (HUS)?

What are the differential diagnoses for Hemolytic-Uremic Syndrome?

Workup

What is the role of lab studies in the diagnosis of hemolytic-uremic syndrome (HUS)?

What is the role of imaging studies in the diagnosis of hemolytic-uremic syndrome (HUS)?

What is the role of biopsy in the diagnosis of hemolytic-uremic syndrome (HUS)?

What are characteristic pathologic findings of hemolytic-uremic syndrome (HUS)?

Treatment

How are the treatment options for Stx-hemolytic-uremic syndrome (HUS)?

What is the role of plasma exchange in the treatment of non-Stx-hemolytic-uremic syndrome (HUS)?

What is the role of monoclonal antibodies in the treatment of hemolytic-uremic syndrome (HUS)?

What is the role of renal transplantation in the treatment of hemolytic-uremic syndrome (HUS)?

What is included in supportive therapy for hemolytic-uremic syndrome (HUS)?

Which specialists should be consulted in the treatment of hemolytic-uremic syndrome (HUS)?

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What dietary restrictions are needed during treatment of hemolytic-uremic syndrome (HUS)?

Medications

Which medications are used in the treatment of hemolytic-uremic syndrome (HUS)?

Which medications in the drug class Complement Inhibitors are used in the treatment of Hemolytic-Uremic Syndrome?

Contributor Information and Disclosures

Author

Malvinder S Parmar, MBBS, MS, FRCPC, FACP, FASN Professor of Medicine, Northern Ontario School of Medicine; Assistant
Professor, Department of Medicine, University of Ottawa Faculty of Medicine; Consulting Physician, Timmins and District
Hospital, Ontario, Canada

Malvinder S Parmar, MBBS, MS, FRCPC, FACP, FASN is a member of the following medical societies: American College of
Physicians, American Society of Nephrology, Ontario Medical Association, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy;
Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald A Sacher, MD, FRCPC, DTM&H Professor Emeritus of Internal Medicine and Hematology/Oncology, Emeritus Director,
Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MD, FRCPC, DTM&H is a member of the following medical societies: American Association for the
Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American
Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood
Transfusion, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Chief Editor

Srikanth Nagalla, MD, MS, FACP Chief of Benign Hematology, Miami Cancer Institute, Baptist Health South Florida; Clinical
Professor of Medicine, Florida International University, Herbert Wertheim College of Medicine

Srikanth Nagalla, MD, MS, FACP is a member of the following medical societies: American Society of Hematology, Association
of Specialty Professors

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alexion; Alnylam; Kedrion;
Sanofi; Dova; Apellis; Pharmacosmos<br/>Serve(d) as a speaker or a member of a speakers bureau for: Sobi; Sanofi; Rigel.

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