Brief
in
Hemolytic Uremic Syndrome
Bernarda Viteri, MD,* Jeffrey M. Saland, MD†
*Children’s Hospital of Philadelphia, Philadelphia, PA
†
Mount Sinai Kravis Children’s Hospital, New York, NY
AUTHOR DISCLOSURE Dr Viteri has disclosed
no financial relationships relevant to this
article. Dr Saland has disclosed that he is
principal investigator for a study related to
type 1 primary hyperoxaluria for Alnylam
Pharmaceuticals. This commentary does not
contain a discussion of an unapproved/
investigative use of a commercial product/
device.
Association Between Hydration Status,
Intravenous Fluid Administration, and
Outcomes of Patients Infected with Shiga
Toxin-Producing Escherichia coli. Grisaru S,
Xie J, Samuel S, et al. JAMA Pediatr.
2017;171(1):68–76
Shiga-Toxin–Producing Escherichia coli and
Haemolytic Uraemic Syndrome. Tarr PI,
Gordon CA, Chandler WL. Lancet.
2005;365(9464):1073–1086
Acute Bloody Diarrhea: A Medical
Emergency for Patients of All Ages.
Holtz LR, Neill MA, Tarr PI. Gastroenterology.
2009;136(6):1887–1898
Complement Activation Is Associated with
More Severe Course of Diarrhea-Associated
Hemolytic Uremic Syndrome: A Preliminary
Study. Karnisova L, Hradsky O, Blahova K, et al.
Eur J Pediatr. 2018;177(12):1837–1844
Hemorrhagic Colitis Associated with a Rare
Escherichia coli Serotype. Riley LW, Remis RS,
Helgerson SD, et al. N Engl J Med.
1983;308(12):681–685
Hemolytic Uremic Syndrome. Sethna CB,
Gurusinghe S. In: Glomerulonephritis.
Trachtman H, Hogan J, Herlitz L, Lerma E,
eds. New York, NY: Springer; 2018
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Thrombotic microangiopathy (TMA) was described by Moschcowitz in 1924, and
the term hemolytic uremic syndrome (HUS) appeared by 1955 to describe a series
of patients with small-vessel renal thrombi, thrombocytopenia, and hemolytic
anemia. During the 1970s an association was noted between enteric Escherichia
coli infections and HUS, and in 1983 the specific trigger of Shiga toxin–producing
E coli (STEC) was recognized. This recognition led to classification of HUS as
“diarrhea positive” or “diarrhea negative,” although this terminology is no longer
popular. Other secondary forms of HUS are known, including HUS associated
with invasive pneumococcal infection, human immunodeficiency virus, systemic
lupus erythematosus, or uncommon reactions to medications such as cyclospor-
ine. More recently, the term atypical HUS (aHUS) has been used to describe a
rare form of HUS occurring in susceptible individuals, most often from defects in
regulation of the alternative pathway of complement, whereas typical HUS largely
refers to STEC-HUS or pneumococcal HUS.
In patients with bloody diarrhea, it is imperative that front-line providers
understand the importance of testing for STEC. In many parts of the world STEC
O157:H7 is the most common pathogen leading to HUS, but it certainly is not the
only one as many other organisms besides E coli have been causally implicated with
HUS. Testing for STEC is evolving quickly. Stool culture, various assays for the
Shiga toxin, and most recently DNA testing of stool are all being used, each method
with its own strengths and limitations. The most crucial issue is timeliness because
the window of opportunity to reduce the morbidity of HUS is limited.
HUS is characterized by microangiopathic hemolytic anemia, with intravas-
cular red blood cell fragmentation seen as schistocytes on peripheral blood smear;
thrombocytopenia; and kidney injury manifesting as uremia. However, the pre-
sentation of HUS can vary considerably, and any organ can be injured, including
the brain, pancreas, colon, and heart. And, in rare cases, the kidneys may be
spared. The differential diagnosis of HUS includes other forms of TMA, includ-
ing thrombotic thrombocytopenic purpura (TTP), which clinically may be nearly
identical.
Whereas bloody diarrhea with STEC infection or a clearly evident infection
with invasive pneumococcus quickly allows the diagnosis of typical HUS with
high certainty, when these infections are not present the etiology of HUS is
unclear without additional investigation. In such patients a presumption of aHUS
is useful because rapid empirical treatment may be curative. Initial diagnostic
steps may include measuring ADAMSTS13 activity and assessing complement
activity and markers of systemic lupus erythematosus. Decreased ADAMSTS13
activity is not uncommon in aHUS, but activity less than 10% is generally
diagnostic of TTP instead. Low levels of C3 are suggestive but not necessary
or sufficient to diagnose aHUS.
Vol. 41 No. 4 APRIL 2020 213
 STEC-HUS is among the leading causes of acute kidney
injury (AKI) in children younger than 3 years. HUS develops
in approximately 15% of children younger than 10 years with
STEC infection, mostly in the summer and autumn. STEC-
HUS has a good prognosis in that most children recover
from the episode, resolving AKI with few if any sequelae.
However, an important minority of patients has acutely seri-
ous or fatal renal and other target organ complications,
such as gastrointestinal or neurologic events, and patients
may, indeed, experience long-term complications, includ-
ing progressive chronic kidney disease and end-stage renal
disease.
Clinicians should have a high level of suspicion for HUS,
particularly in children younger than 10 years who develop
bloody diarrhea, often painful, with or without fever. The
diagnosis of STEC is of key importance because the risk of
developing HUS with STEC infection is reduced when the
microbiological diagnosis is made in a timely manner,
before the onset of HUS, and ample fluid replacement with
isotonic saline is provided. Even in patients in whom
administration of fluids during the period leading up to
HUS does not prevent its development, the severity of the
episode seems to be reduced by the early intervention with
saline fluid. One must be careful, however, to avoid fluid
overload and elevated blood pressure if AKI is unfolding.
Serial renal and hematologic evaluation, including blood cell
counts (especially hemoglobin, platelets, smear, and lactate
dehydrogenase) is required, noting that serum measures of
renal function lag behind actual renal function when it is in
flux. Hematologic manifestations often precede clear signs
of AKI. STEC-HUS usually develops within 1 week (5–13
days) after the onset of diarrhea and commonly within 1 to
2 days of the diarrhea itself resolving. Thus, if the diarrhea
with STEC infection resolves and the patient is stable for 1 to
3 days without hematologic or other manifestation, the risk
of HUS may be considered past.
Another imperative for identifying STEC, as opposed to
other causes of bloody diarrhea, is that the use of antibiotics
with STEC may increase the likelihood of HUS; the current
recommendation is to avoid antibiotics unless another
specific indication for their use supersedes. Nonetheless,
some evidence suggests that the risk is not uniform across
all classes of antibiotics; some (eg, fosfomycin) may actually
reduce the risk of HUS. Future research is needed.
Most children with STEC-HUS require some degree of
symptomatic treatment, but no therapy is proven to ame-
liorate typical HUS once it has developed. Anemia may
214 Pediatrics in Review
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evolve rapidly and require multiple blood transfusions; prac-
titioners should notify the blood bank of this possibility,
which may allow several transfusions from the same unit of
blood, reducing exposure to several different blood donors.
Platelets are usually not given, except for active bleeding or if
a surgical procedure is required. Hypertension is frequent,
but its severity is variable and treatment may range from
minimal to aggressive, with the mandate being to maintain
a safe blood pressure. Minor neurologic manifestations,
such as irritability and headache, are common, but seizures
or altered mental status may herald severe complications
such as ischemia from a large cerebrovascular accident,
diffuse microvascular disease, or hypertensive encephalop-
athy. Any of these may result in permanent brain damage.
Severe AKI may require renal replacement therapy
(RRT), usually peritoneal dialysis or hemodialysis; but in
some cases, hemofiltration may be more suitable. Risk
factors at presentation associated with AKI requiring RRT
include the degree of dehydration, oligoanuria, leukocytosis,
hematocrit concentration greater than 23%, and neurologic
involvement. In turn, the requirement for RRT and its
duration (particularly >3 weeks) are associated with a higher
likelihood of long-term sequelae such as chronic kidney
disease or end-stage renal disease.
The diagnosis of aHUS begins with the same biochem-
ical and hematologic criteria as for typical HUS. Atypical
features include age younger than 6 months, family history
of HUS or recurrence of HUS, absence of diarrhea, or a
slower and insidious onset sometimes preceded by vague
and nonspecific signs and symptoms.
aHUS is predominantly associated with defects of reg-
ulatory proteins that allow increased activity of the alterna-
tive pathway (AP) of complement. Implicated defects
include those that reduce the activity of factor H, factor I,
and membrane cofactor protein, as well as defects that
increase factor B or C3 itself. Defects in thrombomodulin
and vitronectin have been implicated, as have antibodies
against factor H, and the list of such defects may enlarge
or shrink in the future as distinctions between causative
mutations and common genetic variants are disentangled.
However, the general mechanism of these various defects
is shared: intrinsic and triggered activation of the AP
pathway leads to unabated amplification, which results
in endothelial injury and TMA. An exception to this group
is HUS related to a mutation in the DGKE gene, which
regulates an intracellular lipid kinase and is not related to
complement.
 Measurement of AP function and genetic analysis has
improved considerably but still requires more time than
routine biochemical and hematologic testing. Thus, empir-
ical treatment of aHUS is advised pending clarification
of the diagnosis. Eculizumab is a humanized monoclonal
antibody that inhibits complement activation; approved in
North America and Europe for aHUS, eculizumab super-
sedes the use of plasma therapy, which remains indi-
cated when eculizumab is not immediately available. For
patients with aHUS receiving long-term eculizumab ther-
apy, active efforts are underway to better classify and
monitor them to allow selective and safe discontinuation
of treatment.
The role of complement in typical HUS remains
ambiguous, with some evidence that Shiga toxin is able
to activate the AP. One study analyzed 33 patients with
STEC-HUS and found a correlation between C3 levels and
disease severity. Eculizumab has been used in some
patients with severe typical HUS, although definitive evi-
dence to support such use is lacking despite analysis of
its effect either in large STEC-HUS outbreaks or in reported
case series.
and treatment of the disease, I’d like to take the liberty of
recalling my Comment to that earlier article.
Historically, HUS was considered the pediatric sibling of
TTP, a syndrome with similar clinical features but most
commonly affecting adults. However, it turns out that as
much as the 2 may look alike, their parentage is very different.
Typical HUS, the classic form of the disease, is engendered
by a toxin, whereas TTP is the product of an enzymatic
deficiency—the loss of ADAMTS-13, a metalloprotease that
cleaves von Willebrand factor. TTP can be either familial,
when the deficiency of ADAMTS-13 is inherited, or acquired,
when autoantibodies attack the enzyme creating a functional
deficiency. In the absence of customary cleavage, excessively
large multimers of von Willebrand factor build up in the
circulation, causing platelets to aggregate abnormally. The
result is thrombosis, along with thrombocytopenia and its
characteristic purpuric rash: TTP. The thrombi in the micro-
vasculature cause the organ damage that is a feature of both
TTP and HUS, particularly to the kidneys and brain.
Of interest to pediatricians, although TTP is usually
considered a disease of adults, the first case described
almost 100 years ago was the report of a 16-year-old patient.

COMMENT: We last published an In Brief on HUS in 2006. – Henry M. Adam, MD

Although we have since seen changes in our understanding Associate Editor, In Brief

ANSWER KEY FOR APRIL 2020 PEDIATRICS IN REVIEW

Headache in Children: 1. B; 2. B; 3. E; 4. B; 5. E.
Use of C-Reactive Protein and Ferritin Biomarkers in Daily Pediatric Practice: 1. E; 2. E; 3. D; 4. D; 5. B.
Where in the World Did You Get That Rash?: 1. E; 2. D; 3. B; 4. D; 5. B.

Vol. 41 No. 4 APRIL 2020 215

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 Hemolytic Uremic Syndrome
Bernarda Viteri and Jeffrey M. Saland
Pediatrics in Review 2020;41;213
DOI: 10.1542/pir.2018-0346

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 Hemolytic Uremic Syndrome
Bernarda Viteri and Jeffrey M. Saland
Pediatrics in Review 2020;41;213
DOI: 10.1542/pir.2018-0346

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/content/41/4/213

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