Hemolytic Uremic Syndrome PDF

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Hemolytic Uremic Syndrome

Updated: Dec 17, 2013
Author: Robert Stanley Rust, Jr, MD, MA; Chief Editor: Amy Kao, MD
Overview
Background
When Gasser et al first described hemolytic uremic syndrome (HUS) in 1955, it was usually a fatal illness.[1] HUS typically
appeared in early childhood and included the combination of Coombs-negative (nonimmune) thrombocytopenic
microangiopathic hemolytic anemia and irreversible acute renal failure. Survival greatly improved with the advent and
improvement of dialysis and kidney transplantation. However, HUS remains a leading cause of acute renal failure in North
American children and is increasingly recognized as a cause of renal failure in adults. Unfortunately, little advance has been
made in preventing or acutely reversing this most serious aspect of HUS. HUS accounts for 7% of cases of hypertension in
infants younger than 12 months.[2, 3, 4, 5]
Peripheral smear in hemolytic uremic syndrome, with findings of microangiopathic hemolytic anemia. Note
schistocytes/helmet cells, as well as decrease in platelets. Image courtesy of Emma Z Du, MD.
Clinical and pathologic similarities between HUS and thrombotic thrombocytopenic purpura (TTP)–the other major thrombotic
microangiopathy (TMA)–have long been appreciated. However, certain features have been relied on to distinguish most cases
labeled HUS, which is predominantly a disease of children younger than 5 years, from most cases labeled TTP, which is
predominantly a disease of adults. Renal manifestations are more prominent than neurologic ones in HUS, whereas neurologic
findings are more prominent than renal findings in TTP. In industrialized nations, fever precedes the onset of TTP more
commonly than it precedes HUS.[6] In most nonfamilial cases of HUS in industrialized or nonindustrialized nations, dysentery is
an important hallmark of HUS.
The HUS label has long been applied to individuals older than ten years of age who have developed thrombotic
microangiopathy with manifestations that were predominantly renal. Conversely, thrombotic microangiopathy in small children
who have predominantly neurologic manifestations has been labeled TTP. During the early phases of disease recognition,
recognition of atypical cases and difficult-to-classify cases eroded confidence that objective criteria other than age could be used
to distinguish atypical HUS from atypical TTP.
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Two conflicting tendencies followed. The first was awkward expansion of labeled entities within a presumed continuum between
classic TTP and classic HUS. The second was the broad application of a single, nonspecific, and unsatisfactory term TTP/HUS
to cases of thrombotic microangiopathy associated with renal failure and various degrees of involvement of additional organ
systems, particularly the nervous system. The recognition of phenotypic instability in recurrent cases encouraged the tendency
to consider HUS and TTP to be due to the same underlying mechanisms though variously manifested in part because of age-
related vulnerabilities.[7] An example of this apparent phenotypic instability was a patient who had 5 episodes of the HUS
phenotype before the age of 15 years and who had 9 episodes of the TTP phenotype after 20 years of age.[8] However, in 1988
Wardle argued that in most cases, HUS and TTP were separate entities of distinct pathogenesis.[9]
Recent advances in the understanding of the pathogenesis of HUS or TTP have supported Wardle's point of view and have
clarified the boundary between these illnesses and produced useful diagnostic tests to identify discrete processes that clearly
define a particular pathogenic process. However, such tests do not help in distinguishing some clinical syndromes in the TTP-
HUS spectrum. Moreover, the speed of this diagnostic progress has outpaced the establishment of a consensus regarding
diagnostic categories and boundaries. Old systems of classification have been variously amended.
Pending the establishment of a widely accepted system of classification, this article considers HUS on the basis of a tentative
practical system of classification with reference to areas of overlap with TTP, whereas the subject of TTP and its classification is
considered in a separate articles (see Medscape Reference article Thrombotic Thrombocytopenic Purpura).
Pathophysiology
Recent retrospective investigations have demonstrated that some and perhaps most fatal cases of HUS and TTP are
pathologically distinct entities. Both conditions manifest microangiopathy with thromboses. Immune mechanisms play a role in
some instances; however, the microangiopathies of these conditions are primarily the result of different combinations of
developmental, toxic, or mechanical and/or rheologic processes rather than primary immune-mediated processes.
Therefore, the arteriolar and capillary microthrombotic process found in most cases of HUS is the result of the activity of specific
toxins with ensuing injury to endothelial cells. On the other hand, most cases of TTP are the result of one of several possible
abnormalities of platelet function. Microangiopathic anemia is not associated with Coombs positivity in either condition. In both
conditions, it is chiefly the result of rheological disturbances produced by clots. In addition, in HUS, an additional effect of
vascular endothelial swelling occurs.
Both HUS and TTP are families of illness comprising a large core of typical cases and additional atypical examples mediated by
a broad variety of heritable or acquired conditions. Conditions that produce the various atypical forms overlap, and examples of
particular stimuli (eg, verocytogenic Escherichia coli gastrointestinal infection) that classically produce HUS in children younger
than 5 years are described. However, in adults, some of these conditions may provoke TTP. Therefore, these 2 families of
conditions cannot be separated entirely.
In most cases of HUS, the cause is activity of toxigenic proteins that have deleterious effects on endothelial cells, particularly
those of colon and kidney. The 2 most important toxins were initially identified in studies of Shigella dysenteriae and therefore
named Shiga toxin (Stx), specifically Stx1 and Stx2. Because the assay for these toxins used verocytes, they are also called
verocytotoxins (ie, VT-1 and VT-2). In this discussion, these toxins are called Stx1 and Stx2.
Ensuing studies have identified STX (Stx-E coli) as the most important toxic protein in E coli -associated postinfectious HUS
(IStx-HUS). The most commonly identified environmental source of Stx-E coli – producing HUS in humans is the stool of various
animals, particularly cattle, sheep, goats, horses, dogs, domestic fowl, and wild birds, as well as humans. These bacteria are
also found in flies that feed on the feces of these various animals.
Classification
Clinical and laboratory information concerning the presence of infectious agents that may or may not elaborate verocytotoxins,
and tests of ADAMTS-13 enzymatic function or other disturbances associated with TTP (when indicated) permit confident
diagnosis of most cases of HUS. On this basis, TMAs have been classified in several ways, including the following:
Hereditary, recurrent TTP - Idiopathic or ADAMTS-13 deficient
Postinfectious TTP - Acquired, anti-ADAMTS-13 immunoglobulin G (IgG)–mediated
TTP-like illness without identifiable ADAMTS-13 deficiency
Postinfectious HUS - Stx-related (IStx-HUS)
Postinfectious HUS - Non–Stx-related (INon-Stx HUS)
Sporadic or immunologic HUS - Diarrheal and nondiarrheal
Familial HUS - H-factor normal or H-factor deficient
TMA not otherwise specified
As far as HUS is concerned, this classification system is a considerable simplification of old systems of classification. The
overwhelming majority of cases of what might be regarded as typical or postinfectious HUS, ie, microangiopathy and renal
failure after Stx- or non-Stx–elaborating infectious illnesses, with diarrhea more commonly than without. This simplified scheme
readily accommodates these cases, which may be referred to as IStx and non – IStx-HUS. In the venerable Drummond scheme
for the classification of HUS, such cases were called classic infantile HUS or postinfectious HUS and subclassified according to
whether diarrhea was present.[10]
Sporadic or immunologic cases may or may not be associated with a diarrheal prodrome, and they include acquired transient
abnormalities of complement regulation. Clinically defined familial cases are subclassified according to whether the individual is
constitutionally deficient in H factor or activity of the third component of complement (C'3). Non-postinfectious HUS– illnesses
that occur after inflammatory, immunologic, oncologic, endocrine or obstetric, toxic, and other settings are included in the familial
category based on clinical grounds. Otherwise, they are placed in the sporadic or immunologic group. Individuals with TMA in
association with such presumed provocations are identified as having TTP when the clinical and laboratory syndrome is
consistent with that entity. Remaining cases are TMA not otherwise specified.
Stx-related postinfectious HUS, or IStx-HUS
The mechanism of IStx-HUS is increasingly well defined, whereas the mechanisms of INon-Stx HUS is less well understood.
Cases in most young children with a respiratory or other presumed viral prodromes to microangiopathic acute renal failure are
also readily accommodated, especially because specific testing may help in distinguishing such cases from infantile TTP (see
the Medscape Reference articles Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome in Emergency
Medicine).
Most other cases that are likely to represent forms of HUS may be classified as sporadic or familial HUS. Some mechanisms
have been assigned to patients in these groups. Certain provocations associated with HUS are labeled as sporadic or familial.
Identification of a family history of similar events has traditionally permitted the diagnosis of familial HUS. Identification of 1 of
several known heritable mechanisms for the occurrence of HUS should also permit the diagnosis of familial HUS.
Future identification of additional heritable mechanisms will likely increase the percentage of sporadic cases that are transferred
to the heritable category. Individuals with microangiopathic diseases and various combinations of renal, gastroenterologic,
neurologic, and other manifestations that cannot be confidently classified as sporadic or clinically familial acute microangiopathic
renal disease might be identified as having HUS, TTP, or another microangiopathic entity.
Most cases of HUS arise in previously healthy children younger than 5 years and cause the typical combination of hematologic,
gastroenterologic, and renal disease. Most cases occur after an apparently infectious process. Pulmonary findings are not
uncommon, and neurologic manifestations arise in approximately one third of all patients with HUS. These problems tend to be
mild and transient. Most instances of IStx-HUS are induced by E coli (the most common agent in industrialized nations).
Persistent renal disease is unfortunately common and often severe. Outcomes with regard to nonrenal systems are
considerably worsened in Streptococcus pneumoniae – or S dysenteriae type 1–induced Stx-HUS. Most cases of INon-Stx HUS
have a relatively favorable outcome.
In general, the clinical involvement of various organ systems is less widespread in HUS than in TTP. The hemolytic anemia and
associated thrombocytopenia of HUS is typically due to a mechanical microangiopathic processes rather than to some directly
immune-mediated hemolytic process such as that causing a Coombs-positive hemolytic anemia. Coombs testing is negative in
HUS, and the abnormalities of platelet production that characterize most cases of TTP are not found in HUS.
Laboratory testing for heritable or acquired deficiency of ADAMTS-13 activity permits the distinction of most infantile or
childhood cases of TTP from HUS, although the boundary between infantile TTP and HUS is occasionally uncertain. HUS in the
elderly remains a condition for which additional pathophysiologic characterization is necessary. It may well be a condition that
can be differentiated from HUS, the result of unique pathogenicity. HUS-like illness in the elderly tends to be unresponsive to
therapies that are usually effective in childhood HUS.[11, 12]
Postinfectious HUS
IStx-HUS is the largest category of HUS, accounting for as many as 60-75% of all cases of HUS.[13, 14] The 2 important
varieties of toxins are Stx1 and Stx2. These are also called verocytotoxins (hence, the alternative designations VT-1 and VT-2)
because they may be identified by their toxic effects on vero cells. These toxins were initially identified as products of Shigella
organisms, hence the term Stx, although in much of the world, verocytotoxin-producing E Coli (VETC) are the most common
cause of postinfectious HUS.
The toxins are usually elaborated by toxigenic bacteria that have been ingested and that become transiently established in the
colon. In a few cases, other routes of infection (eg, through the respiratory system) establish transient infections with Stx-
elaborating pathogens such as S pneumoniae, the cause of some particularly virulent cases of HUS.
Most cases of IStx-HUS occur in children younger than 5 years and are of gastroenteric origin with associated diarrhea. In
developed regions of the Western hemisphere and Europe, 60-70% of all cases of HUS are caused by Stx-producing strains of
E coli. In nearly 50% of the cases of IStx-E coli HUS, the O157:H7 E coli serotype is found. This particular serotype was termed
enterohemorrhagic E coli (EHEC). However, other enterohemorrhagic serotypes have been subsequently identified, including
026 (25%), 0111 (11%), 0145 (11%), and 0103 (6%). Serotypes 055, 086, 0118, and 0120 together account for less than 1%.[14]
In Argentina and Uruguay, where endemicity of Stx-E coli HUS is highest in the world, the 08, 025, 0112, 0103, 0113, 0145,
0171, and 0174 serotypes are most likely to provoke HUS. Approximately 39% of Argentinian beef cattle are chronically
colonized by E coli manifesting these various serotypes.[15, 16]
In industrialized nations, toxigenic E coli bacteria are ingested from a variety of sources (chiefly water, milk, or foodstuffs
contaminated with fecal material), from contact with animals or their excreta, or from fecal-oral transmission from human to
human. An epizootic reservoir for O157:H7 E coli accounts for the high prevalence of that serotype, particularly in cattle herds
and hence in undercooked hamburger. These examples are frequently responsible for HUS in North America.[17] Recently, a
worrisome trend of increasing prevalence of particularly virulent EHEC has been identified in evolutionary biological studies
carried out in Michigan.[18] These findings offer a possible explanation for recent severe spinach-related outbreaks in the United
States as well as outbreaks of severe HUS in Japan.
Nonevolutionary changes in bacterial genome must also be considered as an explanation. A dramatic increase in EHEC-related
HUS in Sweden was linked to high rates of infection of beef cattle with EHEC. Investigation supported the conclusion that the
increase was due to importation of beef cattle harboring EHEC in their guts. The prevalence was 15% in imported cattle as
compared with 1% in domestic beef.[19] This suggests the importance of public health measures to identify infections in
imported beef.
The finding that as many as 80% of household contacts of children with HUS have circulating Stx supports the feasibility of
human-to-human transmission. Factors beyond mere intestinal acquisition of a toxigenic strain of E coli appears to regulate
susceptibility to HUS. Shedding of toxigenic E coli may persist for weeks in humans or in animals who have acquired the
organism, whether or not they develop diarrhea or other features of HUS.
Ingested toxigenic E coli multiply in the colon. In 38-75% of exposures, cramping and diarrhea ensue after a mean latency of 3
days after ingestion. The diarrhea is initially nonbloody. However, in 70% of patients, it becomes bloody in 1-2 days, and it may
be associated with vomiting. Of note, in the remaining cases of HUS associated with Stx-E coli, no premonitory diarrhea is
observed. In diarrheal cases, large-bowel inflammation occurs, and submucosal hemorrhages often develop, especially in the
ascending and transverse colonic segments. In some instances, toxigenic E coli, particularly the O157:H7 serotype, may induce
hemorrhagic colitis without ensuing HUS.[13, 20, 21]
Particular proteins play roles in establishing intestinal infection and in ensuing inflammation, entry into the bloodstream,
adhesion to circulating cells, and transition to binding at the sites of intimal injury in the kidney and elsewhere. E coli O157:H7
produce an adhesion intimin in addition to Stx1 and Stx2. Intimin mediates attachment of the ingested organism to colonocytes.
Stx2, in turn, mediates attachment to cell surface globotriaosylceramide (Gb3) receptors of other cells, specifically those of
polymorphonuclear cells (PMNs), monocytes, erythrocytes, platelets, and endothelial cells.
Stx2 is the more toxic of the 2 Stxs, and it is the toxin most likely to account for renal disease. Exposure to the Stx1 toxin alone
may provoke diarrhea without associated renal disease. Clinical series show a 55-70% likelihood that acute renal failure will
follow E coli verotoxigenic colitis in children.
Attachment to circulating PMNs appears to be especially responsible for distributing the Stx toxins throughout the body, with
particular apparent tropism for attachment to endothelial receptors in kidney.[22] Stx2 binding to leukocytes is of relatively low
affinity and permits reattachment to other cell surfaces, particularly those of the kidney[23] ; this produces renal dysfunction in
susceptible individuals.
Stx2 binding is particularly likely to occur in blood vessels of the distal convoluted tubules, especially those adjacent to glomeruli
and collecting ducts. Selection of this site in children but not adults may have something to do with age-related expression of
endothelial Gb3 receptors in this particular anatomic location.[24] This particular regional vulnerability may explain the tendency
of HUS TMA to manifest limited organ-system confinement compared with TTP.
Stx1 and Stx2 are made of one A and two small B subunits. One of the B subunits mediates binding to bowel, and a Stx B
subunit mediates binding to kidney Gb3 endothelial receptors. On binding, the A unit is internalized and disrupts endothelial
function by inhibiting protein synthesis. The development and use of specific antibodies to the A subunit to prevent HUS are
among areas of considerable research interest. The disruption of cellular function mediated by the A subunit is the likely
proximate cause of injury to the colonic wall and the renal glomerular endothelium.[25, 26]
The microvascular injury in the kidney appears to provoke a procoagulant state that may not have resulted merely based on
injury to vascular endothelium of the colon. Individuals without substantial renal involvement do not appear to manifest this
same procoagulant picture. Onset of the procoagulant state occurs early in the course of HUS and is indicated by marked
elevation of serum thrombomodulin.[27] Therefore, this elevation is likely a valuable laboratory indicator of the onset of renal
disease. In the converse, decreasing levels of serum thrombomodulin indicate the onset of recovery or renal function.
The marker for the renal phase of HUS pathogenesis is endothelial swelling in the blood vessels of the renal distal convoluted
tubules, which is worsened by the accumulation of proteinaceous material and cellular debris in the vascular subendothelial
space. Thrombus formation ensues. In Stx-E coli –related HUS, the fibrin deposition in clots is explained by activation of both
prothrombin peptide F1+2 and increases the prevalence of the D-dimer before the microangiopathic stage develops.[28]
Flow obstruction likely participates in the formation of the erythrocyte-rich fibrin clots. These clots may entrap some platelets, but
the rate of platelet loss due to this mechanism is far lower than in TTP, in which typically defectively cleaved platelets constitute
a principle element of clots. The pathologic changes of Stx-E coli HUS are typically confined to capillary subendothelial spaces
in the region of the distal convoluted tubules, although in particularly severe cases, thrombi show anterograde propagation into
renal arterioles.
These pathogenic events render portions of the nephron ischemic and compromise function. They also produce a rheologically
unfavorable situation that promotes red blood cell shearing with schistocyte formation.[29]
HUS-associated thrombi are largely confined to the kidney, although they may be found in liver, lung, heart, or brain. Thrombi in
such extrarenal organs tend to produce only mild symptoms. This is unlike TTP, where thrombi are found in heart, pancreas,
kidney, adrenal, and brain (in decreasing order of severity) and often produce signs or symptoms of their presence in these
various organs.[30]
In the most severe forms of IStx-HUS (eg, S pneumoniae or S dysenteriae –associated Stx-HUS), leukocyte entrapment may be
seen. HUS thrombi do not contain the von Willebrand factor (vWF) multimers that are characteristic of ADAMTS-13 deficiency
TTP.[31, 30, 12]
Neither inherited or acquired deficiency of ADAMTS-13 activity, the defining pathogenetic basis of a considerable number of
TTP cases, is a feature of postinfectious or other forms of HUS.[32, 33, 34] Young children with Stx-E coli –associated HUS may
have elevated rates of ADAMTS-13 cleavage of vWF multimers. This, in turn, may result in smaller-than-normal rather than
larger-than-normal vWF multimers.
The enhanced cleavage in HUS may be due to increased availability of ADAMTS-13 cleavage-mediating receptor sites on the
vWF multimers. This may be the result of abnormal unfolding of the multimer receptor site areas due to the increased sheer
stress vWF multimers may experience during circulation through regions containing HUS thrombi and capillary or arterial
microangiopathy.[29]
Other incompletely understood elements are likely to play roles in vulnerability to Stx-HUS. As many as 82% of the household
contacts of a child with IStx-E coli HUS (many of whom have hemorrhagic diarrhea) have Stx bound to their PMNs. Despite this
binding, such individuals often do not have evidence of renal dysfunction. Therefore, an additional mediator is hypothesized to
be necessary for the development of Stx-HUS; this is presumed to be a particular lipopolysaccharide.[35] Why the risk for HUS
in individuals with sporadic Stx-E coli colitis is only 3-9%, while the risk is as high as 20% is some epidemics is unclear.
The observation that the use of an antimotility agent increases the risk for HUS suggests that prolonged contact of organism
with colonocytes or with inflammation-associated PMNs may play an important role in pathogenesis.[21]
The administration of antibiotics, such as trimethoprim sulfa, to children with E coli O157-associated diarrhea may increase their
risk for HUS.[36, 21] The importance of this observation with regard to pathogenesis of HUS is not entirely unclear, although the
possibility that such treatment may increase risk for HUS and the often questionable role of antibiotic treatment of diarrhea have
caused many clinicians to avoid such treatment.
Special circumstances must, however, be considered. In rare instances, individuals may harbor not only Stx-E Coli, but also
Clostridium septicum. This situation may arise as the result of dirty lacerations (in which case localized gas gangrene may
provide an important sign) but may also arise as gut infection in individuals exposed to sheep or individuals with carcinoma of
the cecum. Failure to adequately treat individuals harboring such dual infection has been associated with serious complications
including intracranial C septicum infection.[37]
Levels of C'3 complement are low in approximately one half of all cases of diarrheal HUS; this finding suggests that activation of
the alternative complement pathway occurs in postinfectious HUS.
Acute renal failure, the second and most serious cardinal manifestation of HUS, develops in 50-70% of patients with Stx-
induced hemorrhagic gastroenteritis. Acute renal failure is a potentially life-threatening complication that often leads to
permanently impaired renal function, the principal serious consequence of Stx-E coli HUS.
Insofar as the cerebral manifestations of HUS are concerned, E coli Stx2 induced cerebral microcirculatory endothelial injury in
piglets, suggesting a particular age-related vulnerability.[38, 39] Both arteriolar and capillary thrombi are seen in the brains of 50-
75% of individuals who had fatal HUS, and thrombi are found in their livers and lungs.
In industrialized nations, IStx-HUS tends to occur in mid summer.[40] Undercooked hamburger appears to be a major vehicle for
food-borne E coli O157:H7 outbreaks in children. One study accounted for as many as 46% of cases in children and suggested
an epizootic reservoir.[17]
The other major agent for inducing IStx-HUS is S dysenteriae type 1. It is the major cause of HUS in most nonindustrialized
tropical, subtropical, and some temperate zones of the world. Therefore, it may the most important cause of HUS worldwide,
and it is further distinguished as the cause of the most severe form of HUS. It is acquired by ingesting bacteria from the various
sources likely to contain E coli.
The mechanisms are likely similar to those of IStx-E coli HUS. To these is added the increased probability for prerenal
dehydration or septic shock with Stx-Shig1, which likely worsens glomerular ischemia and which leads to acute cortical necrosis
of kidney. In addition, the comparatively poor availability of intensive medical care in regions with a high prevalence of Stx-Shig1
HUS accounts for the high mortality rate of 30% and the morbidity seen in this form of HUS. Septic shock also plays a role in S
pneumoniae HUS, which may also produce acute cortical necrosis of the kidney.
Other pathogens are associated with diarrhea-associated postinfectious HUS. Among them are toxin-elaborating bacteria such
as Salmonella and Yersinia species. Yersinia organisms may provoke Stx-associated HUS of severity rivaling that due to S
dysenteriae or S pneumoniae. Viruses may provoke early-childhood HUS with diarrhea or a respiratory prodrome (ie, an INon-
Stx HUS). Examples include echoviruses, adenovirus, HIV, or Coxsackie virus.
INon-Stx HUS corresponds to many cases of HUS that were included under the old category of classic infantile HUS. These
cases account for 10% of all cases of HUS in industrialized nations and tend to be infants. A febrile prodrome in the classic
cases is associated with the development of diarrhea. However, bacterial blood cultures are negative and a Stx-elaborating
pathogen is not identified. A viral pathogen is sometimes isolated from appropriate cultures or identified serologically. In other
instances, no associated diarrhea occurs.
Identified viral pathogens include echoviruses or Coxsackie viruses, adenovirus, and HIV. Viruses may directly mediate vascular
endothelial injury in the kidney, but the process is little understood. Likewise, whether the peculiar age-related and regional
vascular susceptibility has the same basis as that which occurs in IStx-HUS is not fully understood. In most cases, HUS tends to
be mild and is likely to have a relatively good prognosis. However, severe cases are described.
In children older than 5 years of age and in adults with HUS, an increased degree of glomerular endothelial abnormality is found
with HUS, and necrotizing arterial thrombosis rather than capillary microangiopathy may predominate.[25] The disease also has
a peculiar tendency to manifest pulmonary thrombosis, which may be seen in early childhood HUS. This is especially prominent
in HUS associated with the use of cyclosporin A or various cancer chemotherapeutic regimens. These thrombi tend to entrap
leukocytes and erythrocytes, and they may be associated with regional tissue necrosis.[41]
Of interest, in some individuals (especially adults), Stx-E coli O157:H7 infection provokes a TTP rather than an HUS phenotype.
[42] Disease in older individuals with HUS is most likely to fit in the sporadic or familial categories of HUS.
Familial HUS
Familial HUS is clinically defined by the occurrence of HUS in 2 or more family members. The occurrence is not usually
associated with diarrhea, although diarrhea-associated cases do occur. Cases of sporadic HUS may be reclassified as familial
when the process is identified in other family members, although co-exposure to Stx-expressing bacteria such as EHEC must of
course be excluded, in which case diarrhea is usually prominent. The first description of familial HUS was provided in 1956,
although the careful studies of Kaplan and associates in 1975 made a considerable additional contribution. Familial HUS is
thought to account for 5-10% of HUS cases.
Recognition of this entity is important because mortality is as high as 50%, despite modern management. This rate is much
higher than the mortality of postinfectious HUS. Thus, severity provides another distinguishing characteristic that may prompt
testing to identify the identification of mutations associated with this form of HUS.
Both autosomal dominant and autosomal recessive patterns of inheritance are described. The pathophysiology of familial HUS
is less well understood than that of postinfectious HUS. Familial cases are subclassified by whether they manifest (D+) or lack
(D-) a diarrheal prodrome. Kindreds may contain individuals who manifest TTP rather than HUS.
Approximately 10-20% of familial or sporadic (D-) cases are associated with mutations in a region of chromosome 1 that
encodes for various complement regulatory proteins. Some familial cases have heritable deficiencies of C'3. Others involve
deficiencies of liver-synthesized complement factor H (HF1).[43, 44] Cases are subclassified according to whether an
identifiable defect in HF1 expression is present. Patients with HF1 mutations tend to have low C'3 levels as well with a mutation
in MCP, a surface-bound complement regulator. Factor H deficiency is associated with type II mesangiocapillary
glomerulonephritis, a particular type of kidney disease, that may develop with or without an HUS presentation.[45, 46] Defective
HF1 expression may be found in affected individuals whose families pass on the disease trait in either autosomal dominant or
autosomal recessive patterns of inheritance.
Individuals with either of these deficiencies tend to have HUS of greater-than-average severity. A missense mutation in the gene
that encodes factor H was identified in some cases of familial HUS[43] , with the subsequent demonstration of genetic
heterogeneity in affected individuals. Furthermore, mutations of this same gene may be associated with familial or sporadic
forms of HUS (defined by the absence of family history) without diarrheal prodrome.[47]
Factor H is a fluid-phase regulator of the activation of the alternative complement pathway, which plays a critical role in
regulating the discernment of host from foreign tissues. The various missense mutations associated with HUS result in
abnormalities in the carboxy terminal of factor H, a region important for binding to C'3 complement receptors and cell-surface
polyanionic structures. Early procoagulant activation is hypothesized to occur, as in diarrheal cases, because of injury to the
endothelial cells. Dysregulation of the alternative complement pathway, due to abnormal binding function of factor H, then
prolongs the abnormal procoagulant state. How defective HF1 expression participates in HUS (or TTP) pathogenesis is not
really understood.
Patients with HUS usually have normal levels of factor H with normal or low levels of complement or C'3.[48, 49] A normal factor
H level does not exclude mutation of the factor H gene. How many cases of (D-) HUS have demonstrable abnormalities in the
factor H gene is unclear. One recent extensive literature review of found factor H gene abnormalities in less than 15% of all
nondiarrheal cases of severe HUS in which a renal transplant was required.
C'3 levels are inversely associated with disease severity and outcome in both (D+) and (D-) sporadic or familial HUS.[50, 51, 52]
Although HUS occurs in individuals with specific abnormalities of only the carboxy terminus of factor H, complete absence of
factor H in pigs, mice, and even humans is not associated with increased susceptibility to HUS. Rather, it portends the possibility
of developing mesangiocapillary glomerulonephritis.[53]
Sporadic HUS
A wide variety of stimuli can provoke endothelial injury with an HUS phenotype. Adults, particularly the elderly are at higher risk
for sporadic HUS than children. Sporadic HUS includes examples of the former immunologic HUS category that are nonfamilial.
It includes HUS with an acute acquired decrease in the concentration of C'3 or a deficiency of H factor activity.[43, 54] A
confusion is that some authorities include some individuals who harbor GI Stx-E coli infections[14] or some who have diarrheal
prodromes in the sporadic category.
However, most cases in the sporadic category do not have an infectious diarrheal prodrome. Among the most common
provocative illnesses are noninfectious vasculitic and inflammatory illnesses, such as Henoch-Schönlein syndrome, systemic
lupus erythematosus (SLE), scleroderma, polyarteritis nodosa, and Wegener granulomatosis. In some individuals, these
illnesses may provoke TTP rather than HUS. In others, they may result in rapidly progressive vasculitic glomerulonephritis rather
than the peculiar glomerulopathies of HUS or of TTP. The elderly are at higher risk for HUS due to these provocations than
children perhaps because of an prevalence of these illnesses and their treatments. However, other age-related factors may also
be at work.
Other provocations of sporadic HUS are malignant hypertension, kidney irradiation, bone marrow transplantation,
immunosuppressants (cyclosporine, tacrolimus, methylprednisolone), snake-venom or diethylene glycol intoxication, and
chemotherapy drugs (eg, mitomycin).[55]
Sporadic HUS due to these stimuli usually occurs without a diarrheal prodrome. The identification of additional individuals in a
kindred who develop HUS due to these or some other provocations listed causes their HUS to be reclassified as familial rather
than sporadic. The reclassification is also true of kindreds in whom familial factor H deficiency is identified.
Tacrolimus-associated HUS, for which renal transplant patients are at risk, tends to arise in adults rather than children. This is
consistent with the general rule that HUS tends to be more severe and difficult to treat in adults than children. Tacrolimus-
associated HUS occurs idiosyncratically slightly more often in men than women and has a mean onset at about 40 years of age
or at about 7 months after receipt of renal allograft. Only 45% of patients improve with various combinations of anticoagulation,
use of antiplatelet agents, dialysis, and plasma exchange.
After HUS develops, tacrolimus is usually replaced with cyclosporine. However, in some instances, an initial dose reduction of
tacrolimus is tried. Graft loss occurs in 25% of patients. Without successful retransplantation, 100% of patients die. Even with
transplantation, approximately one third of patients die. If associated liver failure occurs, 60% die.[56]
The immunologic form of HUS is associated with a decrease in serum concentration C'3, an event that can be detected only
after presentation. Other secondary forms of HUS include those associated with SLE, scleroderma, malignant hypertension,
kidney radiation, immunosuppression, snake-venom intoxication, diethylene glycol intoxication, or chemotherapy with mitomycin
or cyclosporin. Endocrine provocations for HUS include pregnancy and use of oral contraceptives.
Sporadic HUS tends to be associated with greater rates of recurrence and greater prevalence of kidney failure. It is also
associated with an increased risk for seizures and other neurologic complications. It tends to be a severe disease and the
response to supportive therapy may be poor. Hypertension may be severe in affected individuals. Transplantation after sporadic
HUS may be followed by recurrence.
Epidemiology
Frequency
United States
The annual incidence of hemolytic uremic syndrome in the United States is approximately 2.2 cases per 100,000 population.
The highest incidence in the United States is in children younger than 5 years. Incidence as high as 6.1/100,000 population per
year has been estimated for children 5 years of age or younger, although an estimate as low as 1.08/100,000 children less than
5 years of age has been provided.[57] The incidence tends to decline with age, with lowest incidence in adults aged 55-59 years
(0.5/100,000 population per year). HUS may be an under-reported disease. In one study, only 43% of identified cases had been
reported to public health agencies. This California study additionally found that despite strenuous public health measures, the
prevalence of STEC-associated HUS had not changed from the 0.67/100,000 rate.[58]
HUS is associated with verotoxigenic E coli O157:H7, which accounts for nearly half of childhood cases of HUS. This form tends
to occur in midsummer, with most cases occurring between June and September. Summertime predominance is likely to be
found in most other developed nations located in temperate climates.
Undercooked hamburger is a particularly important source of verotoxigenic E coli O157:H7. Undercooked ground meats
processed by using insufficiently cleaned grinders in which beef was previously ground are another course of infection. Milk,
water (from drinking, swimming, or tooth brushing), cider, juices, vegetables washed in water, and human excreta are additional
important sources of infection. Other sources include deer, sheep, goats, horses, dogs, and birds.
Of note, several population-based studies showed that the prevalence of HUS substantially increased in the 1980s in the United
States on the West Coast; this observation may also be true in other developed nations.[59, 13] However, this suggestion was
not supported in one careful study.[57]
When these data are considered with the 40-year increasing prevalence of other autoimmune diseases (eg, juvenile rheumatoid
arthritis, asthma, SLE, multiple sclerosis in women) in industrialized nations, one might conclude that a common set of
influences is disturbing the development of immunoregulation and tolerance. Current research into the genetic and
immunoexperiential factors that determine the competence of immunoregulatory T cells is likely to prove relevant to these
worrisome observations.
International
E coli-related HUS
Data concerning the prevalence of HUS in many parts of the world are incomplete. Consumption of improperly stored or
prepared meats and other foodstuffs in warm seasons or warm climates increases the risk of exposing individuals, especially
children, to Stx-producing E coli. This risk is greatest where sanitation is poor.
Verotoxigenic E coli, particularly the O157:H7 strain, accounts for at least 75% of all cases of postinfectious Stx-HUS in
Western Europe, where the incidence may be on the order of 0.5 case per 100,000 population per year. Incidences in
Scandinavia, Switzerland, and perhaps other individual countries may be lower than this.
In Japan, the O157:H7 Stx strain of E coli is the most important cause of postinfectious HUS.
The incidence of postinfectious HUS prevalence is approximately 5-fold higher in Argentina and Uruguay, at 10.5 cases
per 100,000 population per year, than in the United States. This high prevalence is ascribed to an epizootic reservoir in
Argentine beef, though the manner in which beef is handled and cooked must also play a role in this high incidence.
Stx-E coli are found in approximately 0.6-1.4% of diarrheal stool samples in individuals from Calcutta. However, these
organisms are found in as many as 50% of raw-beef samples from the region. They are overwhelmingly non-O157:H7
strains. In such tropical regions, S dysentaeriae is a more important cause of infectious HUS. However, sometimes
individuals with diarrheal HUS who are found to have Stx-elaborating Shigella in stool have that organism as well as E
coli in blood.
S dysenteriae-related HUS
Data concerning the incidence of S dysenteriae -related postinfectious Stx-HUS is limited. However, in developing nations a
very large number of cases of Shigella Stx-HUS likely occur, with an appalling fatality rate. Shigella Stx-HUS may or may not be
associated with diarrhea, however. One careful study of tropical Shigella -Stx HUS noted diarrhea in 68% of cases and similar
rates of mortality (55%) whether or not diarrhea was present. Among individuals with diarrhea, 16% had neurologic
abnormalities. Shigella Stx-HUS without diarrhea tends to have lower hemoglobin and platelet counts than Shigella Stx-HUS
with diarrhea.[60]
In developing nations, approximately 10 million cases of diarrhea occur in children younger than 5 years. About 1 million
of these children develop dysentery (bloody diarrhea), and approximately 100,000 of these children have Shigella
infection. How many of these children develop postinfectious HUS is unknown.
Travelers' diarrhea particularly occurs in individuals who have visited tropical countries. Travelers' diarrhea represents an
important potential source of sporadic outbreaks of postinfectious Shigella Stx-HUS when these individuals travel to
developed nations.
Between 1993 and 1998, about 5% of individuals returning to Barcelona with traveler's diarrhea harbored enterotoxigenic
Shigella species, chiefly Shigella flexneri or Shigella sonnei. In approximately 20%, the Shigella organism could
elaborate Stx1, the toxin most likely to produce severe dysentery, bacteremia, shock, disseminated intravascular
coagulation (DIC), or HUS. Clustered cases of Shigella Stx-HUS traceable to an index case of traveler's Shigella
dysentery appear to be largely due to person-to-person (fecal-oral) transmission.
North Africa is a region where the risk for severe Shigella Stx-HUS, Stx-sepsis, and shock is increased in children
younger than 5 years.
Mortality/Morbidity
Mortality
When originally described, the mortality rate of menolytic uremic syndrome (HUS) was 50% or greater. Improved supportive
therapy, including transfusion; dialysis; and careful management of fluids, electrolytes, and hypertension, where such
approaches are readily available, have significantly reduced the high mortality rate for children with HUS.
Since the 1970s, the acute case-mortality rate of HUS (including all subtypes) in developed nations has been approximately 5-
10%. A California study of patients hospitalized with HUS showed an acute phase mortality of 2.7%.[58] Comparable data on
children with familial HUS shows an acute phase mortality rate of 5% or higher. The mortality rate for early childhood Asian or
African S dysenteriae HUS may be as high as 30-55%. Severe hyponatremia was identified as a factor predictive of higher
mortality in the Kenyan series.[60] Non–Stx-HUS may have an acute mortality risk as high as 25%, even in developed nations.
Mortality and morbidity rates are distinctly greater in children who develop HUS after a prodromal respiratory illness without GI
disturbance than in those who develop HUS after a diarrheal prodrome. Children who have neurologic signs in association with
HUS are most likely to die or to have residual hypertension or chronic renal dysfunction.
Adults account for a large percentage of non–Stx-HUS cases. They are most likely to have HUS as a secondary complication of
a serious underlying systemic disease; for this reason, the adult case-mortality rate remains higher than that for children.
In tacrolimus-associated HUS, which is chiefly a disease of adults with kidney allografts, graft loss occurs in 25% of all patients.
Without successful retransplantation, 100% of these individuals die. Even with successful retransplantation, approximately one
third die. If associated liver failure is present, 60% die.[56]
Morbidity
The chief morbidity of HUS is chronic renal failure. In the United States, HUS is the leading cause of acquired renal failure in
children. Various degrees of permanent renal injury occur in approximately one third of all cases of HUS. Individuals, usually
children, who develop HUS after an S pneumoniae or S dysenteriae infection are most likely to develop severe kidney
dysfunction and end-stage renal disease due to the renal necrosis and severe glomerulosclerosis.
Only 45% of adults with tacrolimus-associated HUS improve, despite treatment with various combinations of anticoagulation,
antiplatelet agents, dialysis, and plasma exchange. Graft loss occurs in 25% of patients.
HUS accounts for approximately 7% of all cases of hypertension in infants younger than 12 months.
Race
No definite racial predilection for HUS has been identified beyond the elevated risk sustained by individuals of particular
ancestry whose standard of living or place of residence may account for that elevated risk. One study found that white
individuals were more likely than black individuals to be hospitalized for their HUS.[57]
Sex
See the list below:
Some data suggest that girls are at greater risk for sporadic postinfectious HUS than boys are. One study found that
among children younger than 5 years, girls are more likely to be hospitalized for HUS than boys are.[57]
Predominantly an adult disease, tacrolimus-associated HUS occurs slightly more often in men than in women.
Age
Two thirds of all cases occur in children younger than 3 years, and few cases occur after 5 years of age.[14] HUS occurs less
commonly in neonates than in children.
HUS may occur in adults (especially in elderly adults), usually as the result of an identifiable provocation.
Tacrolimus-associated HUS has a mean onset at about 40 years of age or about 7 months after the receipt of a renal
allograft. Other factors governing this apparently idiosyncratic medication reaction are not well understood.
In the elderly, the pathogenesis of HUS usually differs from that of HUS in childhood. Elderly individuals respond
relatively poorly to support and management that are effective in childhood cases.[11, 12]
Presentation
History
See the list below:
Hemolytic uremic syndrome (HUS) may arise as a familial or an idiopathic illness, and it may or may not be associated
with an identifiable prodrome or provocation.
Postinfectious HUS is more common than heritable forms of HUS. Postinfectious HUS may occur after infections by
viruses or bacteria, and the prodromal manifestation often includes diarrhea.
Viruses isolated in cases of HUS include echoviruses, adenoviruses, and coxsackieviruses. Identified bacterial
organisms include Salmonella, Shigella, Streptococcus, and Yersinia species.
In some instances, the presence of an exanthem or enanthem may assist in identifying a particular infectious agent. An
example is a coxsackie rash associated with fever and diarrhea before the onset of renal failure.
Diarrhea-associated postinfectious HUS is most likely to occur in children younger than 5 years. It represents what
Drummond called "classic infantile" cases. Children uncommonly have a nondiarrheal prodrome, usually as a respiratory
infection or sepsis.
In industrialized nations, verotoxigenic E coli O157:H7 appears to be the most important cause of postinfectious HUS.
This is usually heralded by the development of hemorrhagic colitis. In one study, this particular serotype of E coli was
identified in 46% of children with classic infantile postinfectious HUS.
HUS due to this agent has a distinct midsummer seasonal predilection.
A history of consuming undercooked cooked ground beef is the most important risk factor with E coli O157:H7
infection; this finding suggests an epizootic reservoir.
Relatively uncommon routes of acquisition include exposure to contaminated water or milk and fecal-oral routes
from human or animal sources.
Various degrees of cramping abdominal pain precede the onset of diarrhea by days to weeks.
Vomiting occurs in 30-60% of patients.
Diarrhea is usually non bloody at the outset. However, in approximately 38-70% of cases involving E coli O157:H7, the
diarrhea becomes hemorrhagic within 1-2 days. Approximately 3-9% (up to 20% in some epidemics) of children who
have this course develop overt HUS.
A history of using antibiotics, such as trimethoprim sulfa or antimotility agents, increases the risk of HUS with
verotoxigenic colitis.
Abdominal pain and fever may be severe. Severe abdominal tenderness or prolonged vomiting may suggest pancreatitis,
and a surgical abdomen suggests the possibility of bowel infarction.
In nonindustrialized nations, the most important cause of hemorrhagic enterocolitis is Shigella dysentery type 1.
Patients may have a history of residing in or traveling to areas where S dysenteriae or Yersinia infections is endemic.
Patients may have a history of having contact with another person, particularly a child, who traveled from an endemic
area and who developed dysentery.
Dysentery due to S dysenteriae or Yersinia organisms may be severe.
Children without diarrhea may have had a prodromal respiratory illness or sepsis; these children have a prognosis
distinctly worse than that of patients with a diarrheal prodrome.
Patients may have a history of severe fever.
A variety of noninfectious processes may precede sporadic cases of HUS. Many of these processes arise more
commonly in adults than in children. Patients may have a history of the following:
Henoch-Schönlein purpura
HIV infection or AIDS
Systemic lupus erythematosus (SLE)
Antiphospholipid antibody syndrome
Scleroderma
Polyarteritis nodosa
Wegener granulomatosis
Malignant hypertension
Kidney radiation
Bone marrow or stem cell transplantation
Various organ allograft kidney transplantations, usually more than 7 months before HUS
Immunosuppression with cyclosporin, tacrolimus, or methylprednisolone (Tacrolimus-associated disease is usually

seen in individuals older than 40 years, more commonly in men than in women.)
Pancreatic cancer treated with gemcitabine
Cancer treated with mitomycin or other chemotherapy drugs
Snake envenomation
Diethylene glycol exposure
Pregnancy or use of oral contraceptives
Familial and sporadic forms of HUS need not be preceded by diarrhea or another definable illness (other than fatigue,
irritability, and lethargy).
Physical
Physical findings depend on the nature of the prodromal illness and the degree to which various organ systems are involved in
the HUS phase.
Fever may be present.
Skin changes include the common finding of pallor. The patient's skin may be dry or doughy if they are dehydrated, and
mucous membranes may be dry in such patients.[61]
Pulmonary findings may reflect a respiratory prodromal illness to postinfectious HUS, or it may be the consequence of
renal failure or CNS, cardiac, or pulmonary involvement in HUS.
Postinfectious HUS with diarrheal prodrome may produce abdominal tenderness.
Colonic ischemia may be severe enough to represent a surgical emergency.
Abdominal tenderness is occasionally due to the development of pancreatitis.
Patients develop acute renal failure and enter a catabolic state with acidemic uremia and hypertension.
Neurologic manifestations, most commonly behavioral changes, motor seizures, and encephalopathy, are seen in 30-
40% of children with classic postinfectious HUS with a diarrheal prodrome. Such manifestations are more common in
familial cases.
Blindness, ataxia, hemiparesis, coma, and decerebrate rigidity are reported. Neurologic findings such as these indicate a
poorer prognosis.
Whether neurologic changes are the result of cerebral microangiopathy or secondary to metabolic disturbances and
hypertension is not always clear.
Causes
The various known causes of HUS are also discussed in the Pathophysiology and Clinical sections.
In brief, postinfectious HUS is due to viruses (eg, echoviruses, adenoviruses, coxsackieviruses) and bacteria (eg, Salmonella,
Shigella, Streptococcus, and Yersinia species, as well as verotoxigenic E coli O157:H7).
In one study, the O157:H7 serotype of E coli was identified in 46% of patients. Undercooked hamburger appears to be a major
vehicle for food-borne E coli O157:H7 outbreaks in children, suggesting an epizootic reservoir. Several adult cases of TTP have
been associated with the same pathogen, though this association is less common in adults than in children. Use of an
antimotility agent or trimethoprim-sulfamethoxazole (TMP-SMX) appears to increase the risk for HUS. Data from preliminary
studies suggest that the use of SYNSORB-pk may be effective in absorbing verotoxin in the intestine, preventing HUS.
The immunologic form of HUS is associated with a decrease in serum concentrations of C'3, an event that can be
detected only after presentation. Other secondary forms of HUS include those occurring in association with SLE,
scleroderma, malignant hypertension, kidney radiation, immunosuppression, snake-venom intoxication, diethylene glycol
intoxication, or chemotherapy with mitomycin or cyclosporin.
Endocrine causes include pregnancy and use of oral contraceptives.
DDx
Differential Diagnoses
Neonatal Meningitis
Neurologic Disease and Pregnancy
Neurological Manifestations of Uremic Encephalopathy
Neurological Sequelae of Infectious Endocarditis
Neurosarcoidosis
Polyarteritis Nodosa
Primary CNS Lymphoma
Systemic Lupus Erythematosus (SLE)
Thrombotic Thrombocytopenic Purpura (TTP)
Viral Encephalitis
Viral Meningitis
Workup
Workup
Laboratory Studies
See the list below:
Hemolytic uremic syndrome (HUS) is fundamentally a microangiopathic nonimmune hemolytic anemia associated with a
variety of complications. Microangiopathic Coombs-negative hemolytic anemia and acute renal failure with microscopic
hematuria and proteinuria (1-2 g/dL) abruptly mark the onset of HUS in nearly all patients.
Hematologic and associated serologic findings of HUS thrombotic microangiopathy (TMA) (and thrombotic
thrombocytopenic purpura [TTP]) include the following:
Anemia: Anemia is an invariable finding and usually severe, whether HUS occurs after postinfectious
verocytotoxin-related colitis (eg, due to E coli or S dysenteriae) or in HUS without a diarrheal prodrome (eg,
related to S pneumoniae pneumonia or sepsis).
Thrombocytopenia: Platelet counts tend to be somewhat higher in HUS TMA than in TTP because they are not
consumed quickly by clot formation. However, in some cases of HUS, thrombocytopenia may be severe.
The microcirculatory clots of TTP are formed in large part from platelets, whereas those that develop in
HUS consist chiefly of red blood cells. The HUS clots are fibrin rich but contain relatively few platelets.
Severe HUS GI bleeding is associated with consumptive thrombocytopenia.
Platelet survival time is shortened in HUS.
Platelet counts may be < 80 X 109/L (< 80,000/mm3).
Additional findings include the following:
Microangiopathic changes occur in RBCs.
The peripheral blood smear reveals fragmented RBCs (eg, schistocytes, spherocytes, segmented RBCs, burr cells,
helmet cells).
Reticulocytosis (proportional to hemolysis) and circulating free hemoglobin may be found, though not when bone marrow
response to anemia is impaired.
Increased serum thrombomodulin levels may be found and are a marker for endothelial injury in HUS.
Leukocytosis may be found.

In postdiarrheal cases, moderate leukocytosis typically develops and may be an indicator of renal failure.
In cases arising after a respiratory prodrome or S pneumoniae sepsis, early and marked leukocytosis may be found with
abundant immature forms.
Because hemolytic anemia is nonimmune, results of Coombs testing is negative.
HUS is more likely than TTP to manifest changes consistent with disseminated intravascular coagulopathy (elevated
fibrin split products, prolongation of the activated partial thromboplastin time, and low antithrombin III levels).[62]
Full-blown disseminated intravascular coagulation (DIC) is especially likely in S dysenteriae –related postinfectious HUS.
Of interest, TTP occurring after verotoxigenic E coli O157:H7 infection in adults may provoke changes consistent with
DIC.
Fibrinogen levels may be normal or increased.
Because of intravascular hemolysis, direct bilirubin values are elevated, where haptoglobin levels are usually low.
The most sensitive indicator of ongoing intravascular hemolysis is an elevated serum lactate dehydrogenase (LDH) level,
and tissue ischemia may further elevate the value.
Evidence of inflammatory changes may be found in blood and urine.
Diminished serum concentrations of C'3 is found in approximately half of all cases of verotoxigenic E coli –related HUS.
In the acute situation, the extent to which low levels of C'3 reflect a heritable defect of complement C3 or factor H may
not be clear.
Elevated concentrations of alpha-1 and beta-2 microglobulins may be found in the urine.
In HUS with a diarrheal prodrome, bacterial or viral stool cultures may yield verotoxigenic E coli, S dysenteriae,
coxsackie virus, echovirus, Salmonella enteritis, or Yersinia species.
In North America or Europe, at least 70% of all cases of postinfectious HUS with diarrheal prodrome are due to E coli
enteritis. This can be confirmed with stool cultures, and the specific serotype may be identified. Most of these cases
occur in children younger than 5 years.
O157:H7 is the most common Stx-elaborating serotype of E coli. Absence of sorbitol fermentation of the subcultured E
coli is a strong indication of this serotype, which may be confirmed with specific serotyping.
The relatively uncommon O26, O103:H2, O111:H8, O121, O145, and other serotypes have been identified as Stx+ E coli.
Culture and other findings
In Asia, North Africa, and many developing nations in tropical or temperate zones, cultures may demonstrate
enteric infection with Stx-elaborating S dysenteriae. Serotype 1 is by far the most common cause of HUS.
Stx+ S dysenteriae –related HUS more commonly occurs in children younger than 5 than in adults.
Associated bacteremia is not uncommon.
Throat cultures may yield S pneumoniae or adenovirus in individuals with a respiratory prodrome.
Blood cultures may yield S pneumoniae in infants presenting with nondiarrheal sepsis.
Infants or young children presenting with S dysenteriae postdiarrheal HUS are sometimes septic.
Stx may be identified in stool in postinfectious HUS with diarrheal prodrome.
Hematochezia is common in verotoxigenic HUS (related to E coli or especially S dysenteriae), particularly when
consumptive coagulopathy is severe. This enteric bleeding is presumably due to the microangiopathy with
associated thrombosis of enteric circulation.
Because of the particular predilection for involvement of renal microvascular circulation, acute renal failure is
routinely found in Stx+ or non-Stx HUS with resulting elevation of blood urea nitrogen (BUN) and creatinine levels.
Microscopic hematuria and proteinuria of 1-2 g/dL develop abruptly as consequences of renal failure in 25% or
more of patients with HUS.
Alpha1- and beta2-microglobulins may be found in the urine of individuals with HUS-associated renal failure.
The mean glomerular filtration rate for classic Stx-E coli HUS is less than 80 mL/min/1.73 m2 body surface area.
Marked acidemic uremia may result from the combination of acute renal failure and catabolic state. Approximately
one third of these patients become anuric.
Hypertensive cardiac failure may add prerenal kidney failure to renal failure.
HUS associated with illnesses other than verotoxigenic infections, sepsis, or other infectious processes may
provide additional clues to the pathogenesis. However, many patients with such symptomatic have a premorbid
history of such conditions.
Malignancies associated with the development of sporadic HUS may produce various diagnostically significant
changes in the appearance of the blood film and blood counts.
HUS associated with the use of antineoplastic or immunosuppressive agents may provoke marked
leukocytopenia.
Particularly low platelet counts may be seen in HUS associated with the use of immunosuppressive or
antineoplastic drugs.
Strikingly low platelet counts may be seen in pregnant women with hemolysis, elevated liver enzyme levels, and
low platelet count (HELLP) syndrome
Biochemical changes reflecting the hepatopathy that is another cardinal feature of HELLP may also be found.
Among non-Stx (sporadic) cases of HUS, immune-mediated forms are associated with a decrease in the serum
concentration of C'3 at the onset of disease. This decrease may be particularly striking when HUS occurs in
association with an identifiable systemic inflammatory disease, such as SLE or scleroderma.
Various laboratory abnormalities are seen in cases of HUS that involve the liver. These represent dysfunction
associated with hepatic microvascular disease.
Hypercalcemia is common in HUS.
Familial non-Stx HUS accounts for less than 3% of all cases of HUS and tends to produce particularly severe
microangiopathy and renal failure.
Remarkably low levels of C'3 may be found. This deficiency may persist during remissions of HUS.
Any of more than 50 mutations of the HF1 (factor H) gene (on chromosomal region 1q32) may be found in up to
40% of all cases of familial non-Stx HUS and in as many as 13-17% of all cases of sporadic non-Stx+ HUS. In the
latter case, it probably occurs as an acquired autoimmune HF1 defect due to anti–factor H antibodies.
Factor H is an important regulator of the alternative pathway of complement. It is a cofactor for the cleavage of
C3b by C3b convertase. Of interest, defects in HF1 are observed in some cases of thrombotic TTP.
Other causes of non-Stx+ (sporadic) HUS that can be diagnosed with various laboratory tests. These causes
include S pneumoniae (40% of all cases of non-Stx+ HUS), Neisseria meningitidis, and other bacteria. Systemic
viral infections may be diagnosed by using blood, oropharyngeal, or rectal cultures and/or viral titers.
Particular tests may reveal non-Stx (sporadic) HUS due to systemic autoimmunity. Important examples are SLE,
antiphospholipid antibody syndrome, and scleroderma.
Other conditions that may provoke the development of non-Stx (sporadic) HUS are usually identified based on the clinical
history. These conditions may have their own associated clinical or laboratory changes or abnormalities in addition to
those characteristic of HUS. These conditions include the following:
Pregnancy, particularly in individuals with preeclampsia or the syndrome of hemolysis, elevated liver-enzyme levels, and
low platelet count (HELLP syndrome)
Diethylene glycol intoxication
Use of anticancer drugs (eg, cisplatin, mitomycin, bleomycin, gemcitabine)
Use of immunomodulatory drugs (eg, cyclosporine, quinidine, interferon, tacrolimus, OKT3)
Use of antiplatelet drugs (eg, ticlopidine, clopidogrel)
Imaging Studies
See the list below:
Overview
The organs and system most likely to show imaging changes in association with HUS are the kidneys and the GI
tract.
Patients with neurologic abnormalities may or may not have imaging abnormalities initially, though initial or follow-
up studies may show a variety of changes.
Abnormalities in organs other than the kidneys and those of the GI tract may be observed initially, during acute
illness, or with delayed onset during the recuperative period.
Enteric abnormalities
Marked thickening of the intestinal wall may be observed during the enteritic, or especially the enterohemorrhagic,
phase of illness, which usually precedes acute renal failure.
Such changes are usually observed when serious enteropathy is initially suspected and when the diagnosis of
HUS or related entities is considered. At this time, typically 4-6 days after the onset of diarrhea, initial enteric
imaging is usually undertaken.
Abdominal imaging with barium enema may show thumb-printing of the large bowel due to the combination of
edema of the bowel wall and submucosal hemorrhage. These changes are usually most striking in the ascending
or transverse colon.
HUS rarely occurs after Clostridium perfringens sepsis with multiple organ failure, in which case imaging
abnormalities are particularly severe and fulminant. In such cases, imaging findings may suggest regional enteritis
of the Crohn type.
Renal findings
At the onset of acute renal failure, which occurs in 55-70% of cases of HUS, a variety of imaging techniques may
be used to evaluate the etiology and nature of renal impairment. Most abnormalities observed are not specific for
HUS; hence, considering the changes observed in the context of the case history and available laboratory results
is important.
Increased brightness of the kidney may be detected on renal ultrasonography.
In patients with HUS, ultrasonography combined with Doppler imaging may demonstrate the association of 2
findings: diminished parenchymal perfusion and an increased resistance index (RI). This combination is found not
only in HUS but also in TTP, panarteritis nodosa, and other vasculitic nephropathies.[63]
Cortical necrosis of the kidney is observed in many instances of severe HUS, as seen in association with S
dysenteriae or S pneumoniae infections.
Neurologic findings
In patients with neurologic manifestations associated with HUS, various abnormalities may be observed on brain
images.
In North America and in Europe, most patients with clinical and radiographic abnormalities involving the nervous
system will have had verocytogenic E coli HUS. Approximately one third of these patients have serious neurologic
symptoms or signs.
MRI of the brain may reveal focal areas of infarction with swelling and, in some cases, hemorrhage, especially in
areas such as the internal capsule and deep gray nuclei. Whether changes observed on images are due to
cerebral microangiopathy or hypertension and metabolic disarray is not always clear.
Limited evidence shows that approximately 60% of patients with chiefly verotoxigenic E coli and clinically
significant neurologic findings have abnormalities on brain CT or MRI during the acute phase. However, in 40% of
patients, CT and MRI images are entirely normal.
The most common sites of abnormality on CT or MRI during the acute phase of HUS are the thalami, brainstem,
or cerebellum. In one series, 1 or more of these locations were involved in 60% of cases of HUS with MRI
abnormalities. In approximately 20%, abnormalities were in 1 or both thalami; in 20%, in the cerebellum; and in
10%, in the brainstem. In some instances, lesions contained hemorrhage.[64]
In 1 small series, all abnormalities resolved in nearly one half of all children with good clinical outcomes after
verotoxigenic E coli HUS; slightly more than one half had partial resolution at the time of imaging follow-up.[64]
Favorable clinical and imaging improvement may be seen, even in patients with severe initial clinical and imaging
abnormalities. On follow-up imaging, a hemorrhagic component in an area of acute abnormality may be the best
predictor of a residual imaging abnormality.
The prevalence of neurologic involvement with associated imaging abnormalities is clearly lower in HUS after
verotoxigenic E coli enteritis than after the comparatively rare HUS related to S pneumoniae infection.
Although little pertinent information is available, imaging techniques are least likely to show improvement in HUS
after verotoxigenic S dysenteriae enteritis among all types of postinfectious HUS.
Verotoxigenic S dysenteriae HUS is by far the most prevalent type of HUS in developing nations, where CT and
MRI may not be readily available.
In S pneumoniae –related HUS, the risk for CNS involvement is high. MRI is more sensitive than CT for detecting
brain abnormalities. The findings are usually associated with acute bacterial meningitis, which is the cause of
death in most patients with S pneumoniae –related HUS. Examples of such findings are listed below.
MRIs obtained with a long repetition time (TR) and a short echo time (TE) (intermediate) show abnormal
hyperintensity in the brain cisterns and near the base of the brain.
On fluid-attenuated inversion recovery (FLAIR) imaging, increased signal intensity throughout the
subarachnoid spaces is due to increased cellular and protein content in CSF.
On FLAIR imaging, contrast enhancement in the meninges is due to leak of contrast agent from inflamed
blood vessels.
Abnormalities of the cerebral parenchyma subadjacent to the meninges may be due to inflammation or
infarction.
Subdural effusions may be observed.
Pulmonary findings
Several types of lung abnormalities have been described in individuals with HUS.
Acute pneumonia is commonly found in patients with non-Stx (sporadic) HUS related to S pneumoniae.
One 20-month-old Italian infant developed pulmonary hemorrhage after the acute phase of postdiarrheal HUS,
although he had greater degrees of thrombocytopenia and coagulative abnormality during the acute phase that
had resolved.
Procedures
See the list below:
In kidney biopsy specimens obtained from patients with acute Stx+ HUS, the predominant finding is in the glomerular tuft.
These changes apparently develop early in the course of illness.
Changes include microvascular endothelial swelling with an accumulation of proteinaceous material and cellular
debris in the subendothelial layer (between the inner endothelial cell membrane and the subadjacent basement
membrane).
Microthromboses may be found in the involved microcirculation of the kidney near the glomerular tuft.
These microthromboses include fibrin thrombi that may occlude the glomerular tuft.
In some instances thrombi extend likely because of retrograde propagation of clot into the arterioles.
Renal cortical ischemic disease may be found in severe cases of Shigella dysenteriae or HUS related to S pneumoniae.
Histologic Findings
Biopsy findings are noted above.
Treatment
Medical Care
Management of HUS is supportive and chiefly involves dialysis for individuals with renal failure. Acute medical issues involve the
management of renal failure and hypertension, the maintenance of fluid status in the face of renal failure, and the treatment of
fever and catabolic status. Adult HUS and its underlying illnesses respond poorly to various forms of medical therapy.
Among the therapeutic options considered in adults are anticoagulation; antiplatelet or antioxidant agents; fibrinolytics;
thrombolysis (with streptokinase); plasmapheresis and plasma exchange; and infusions of plasma, prostacyclin, or gamma
globulin.[65, 66, 67] None of these approaches has been proven effective beyond excellent supportive care. Plasma
manipulations do not appear to have the same degree of benefit in HUS as such manipulations have shown in TTP.[68] Among
other forms of therapy that have been tried in adults, prednisone, azathioprine, vincristine, and intravenous immunoglobulin
(IVIg) are the medications for which the evidence of efficacy is strongest.
Eculizumab
Eculizumab (Soliris) is the first treatment approved by the US Food and Drug Administration (FDA) (September, 2011) for adults
and children with atypical hemolytic uremic syndrome (aHUS). Approval was based on data from adults and children who were
resistant or intolerant to, or receiving, long-term plasma exchange/infusion. Data also included children (aged 2 mo to 17 y) who
received eculizumab with or without prior plasma exchange/infusion. Eculizumab demonstrated significant improvement in
platelet count from baseline (P = .0001). Thrombotic microangiopathy events were reduced, and maintained or improved kidney
function was also reported.[69, 71, 72, 73]
Antibiotics
The value of antibiotics has been debated. Antibiotics may be required where sepsis or lung infections complicate HUS, as in
HUS associated with S pneumoniae infection. In 1 study, antibiotic treatment in the acute enteric stage of E coli enteritis
increased the risk for HUS 17-fold.[36] A meta-analysis did not show such an effect. In 1 adult with E coli O157:H7 bacteremia
and urinary tract infection who developed HUS, both renal and hematologic abnormalities promptly improved with antibiotic
treatment. Antibiotics may be lifesaving in patients with S dysenteriae –related HUS if started early enough. The treatment of
sepsis associated with S pneumoniae HUS is similarly important.
Transfusion
Blood transfusion is required in as many as 70-90% of children with postinfectious HUS, particularly those with hemorrhagic
colitis. Platelet transfusion is necessary in about 30% of children with HUS.
Although some regard platelet transfusions as dangerous in TTP, as many as 30% of patients with HUS receive platelet
transfusions in addition to other supportive therapies.
Management of blood pressure
Blood pressure support is required for individuals who develop septic shock. Shock occurs in more than 30% of individuals with
S dysenteriae –related HUS and in some patients with sepsis due to S pneumoniae –related HUS.
Arterial hypertension develops in two thirds of patients and is often severe. Arterial hypertension may lead to cardiac failure and
pulmonary edema.
Management with antihypertensives may be important in the management of HUS-associated posterior leukoencephalopathy.
Plasma treatment
Plasma administration and manipulations appear to be less beneficial in HUS than in TTP.
Plasma treatment has been particularly advocated in HIV-associated HUS and in HUS occurring as a postpartum complication.
It has been used in sporadic idiopathic non–Stx-HUS; HUS as a complication of antineoplastic, antiplatelet, or
immunosuppressive drugs; and in sporadic or familial HUS associated with abnormalities of complement pathway regulatory
proteins, such as factor H, membrane cofactor protein (MCP), and factor I.
Anticoagulation
Anticoagulation, which is sometimes attempted in adults with HUS, entails risk in children because childhood HUS is frequently
complicated by both bleeding and hypertension. Where tried, anticoagulation does not appear to be beneficial, even when
combined with oral antiplatelet agents. Indeed, heparin therapy may significantly increase mortality;[74, 75] therefore, this
approach is probably contraindicated.
Adsorption
Investigations have been undertaken to evaluate the effectiveness of administering preparations containing inert adsorptive
surfaces that can bind circulating verocytotoxin and thereby prevent their attachment to endothelial surfaces, where they can
cause injury. SYNSORB-pk ingestion was among the first approaches tried.[21] Despite initial enthusiasm, this approach
appears to have been abandoned. Other similar preparations have also been evaluated, but none have been effective.[76]
About one third of patients become anuric. In combination with their catabolic state, severe acidemic uremia may develop.
Renal failure usually persists for several weeks, and 30-50% of patients require dialysis.
Angiotensin-converting enzyme (ACE) inhibitors used in the treatment of hypertension appear to have a beneficial effect on
renal outcomes of postinfectious Stx– E coli HUS.[77]
Other medical therapies
Trials of gamma globulin are under way, with promising preliminary results. Findings suggest the possibility of some benefit in
children.
Azathioprine and vincristine are potent drugs with potential benefit in the management of HUS. Their use falls beyond the scope
of this review. Oncologists or others familiar with the use of these drugs should be consulted to review the emerging data about
safety and efficacy in HUS and to discuss the risks and principles of management before these agents are administered.
About 25% of patients with HUS who develop neurologic complications (eg, seizures, stroke, coma) may require intensive care.
A small study in Germany used immunoadsorption to rapidly ameliorate severe neurological complications in patients with E
Coli 0104:H4-induced HUS.[78] Of the 12 patients enrolled, 10 had total neurological and renal function recovery.
Anticonvulsant therapy may be required to control seizures.
HUS occurring in association with tacrolimus occasionally responds to lowering the dose.
Consultations
See the list below:
Pediatric or adult renal specialists should be consulted to manage renal failure.
Pediatric or adult rheumatologists should be consulted in cases of HUS associated with neoplasia.
Pediatric or adult hematologists may be consulted for the diagnosis and management of hematologic aspects of HUS.
Pediatric infectious disease specialists may be consulted for the diagnosis and management of associated infectious
illnesses.
Pediatric gastroenterologists may be consulted for the management of associated gastroenterologic disease.
Diet
Special dietary consultation may be necessary to manage renal or gastroenterologic manifestations of HUS. In patients with
renal failure, early reduction in protein intake appears to improve long-term renal outcomes.
Activity
See the list below:
Individuals who are shedding infectious agents that elaborate Stx or who may spread other contagions should be
restricted, as appropriate for the particular infectious agent.
No other specific limitations on activities are needed, except as indicated by the severity of disease and the patient's
need for support. Therefore, activities should be advanced as tolerated.
Follow-up
Further Outpatient Care

Support groups for individuals with HUS have been formed. A British example is Hemolytic Uremic Syndrome Help (HUSH).
This group may be contacted at PO Box 1303, Loxley, Sheffield, England S6 6YL.
Deterrence/Prevention
E coli –related HUS is a serious but almost entirely preventable disease.
Careful practices in slaughterhouses and the butcher shops can prevent the contamination of meat products.
Washing of other raw foodstuffs should substantially reduce risk of E coli entering the food chain.
Personal sanitation by food handlers reduces the risk of transferring E coli to foodstuffs, particularly raw meat.
Consumption of contaminated meat is the primary route by which children in developed nations acquire the organism.
If the aforementioned safeguards fail, adequate cooking of meat prevents children who are most subject to HUS from
acquiring viable organisms.
Meat should be cooked to at least 70°C. Cooking that imparts a gray color to raw hamburger is not adequate.
E coli may also be acquired by bathing in contaminated lakes, rivers, or even swimming pools. This form of exposure
may be more common in certain developing or impoverished areas of the world.
Complications
Although approximately 80-85% of patients who have acute renal failure with Stx-HUS recover function, 15-20% develop
hypertension within 3-5 years after the onset of acute HUS.
Prognosis
See the list below:
Overall: Improved supportive therapy, including transfusion, dialysis, and careful management of fluids, electrolytes, and
hypertension, has substantially reduced acute mortality from HUS.
Infants and children
The infantile form of HUS preceded by a viral prodrome, and usually associated with diarrhea, has a relatively
good prognosis.
Childhood forms of HUS carried a 50% mortality risk half a century ago. Pooled data obtained since 1950 (chiefly
consisting of E coli –related HUS) demonstrate that the overall risk for death or end-stage renal disease is about
12%, including 3-5% risk of death in the acute phase of illness . The inclusion of studies from a period prior to the
development of current methods of neurologic and renal intensive care likely paint a poorer picture of outcome
than is currently enjoyed by individuals with HUS.[79, 80, 3]
In children who develop HUS after a prodromal respiratory illness without GI disturbance, the prognosis is
distinctly worse than that of children who develop HUS after a diarrheal prodrome.
Renal transplantation is necessary in severe HUS, which accounts for approximately 25% of all childhood cases.
Adults
Adult mortality in both the acute and chronic phases of illness are high, probably because adult HUS most often
occurs as a complication of systemic illnesses that are more severe than those encountered in children with HUS.
Pooled data from 3476 cases of HUS followed up for a mean interval of 4.4 years showed a 12% risk of death or
development of end-stage renal disease after the acute phase of HUS.
Risk factors for a worsened long-term outcome, particularly with E coli -related HUS, are the severity of the initial
illness, the need for initial dialysis, and the presence of neurologic signs or complications.
S dysenteriae -related HUS poses a considerable risk of bacteremia or septic shock, DIC, and acute cortical
necrosis of kidney. The overall mortality rate is at least 30%; the risk for end-stage renal disease is also high.
HUS-associated renal failure usually persists for several weeks.
About 30-50% of patients require dialysis, which indicates a worsened prognosis.[13]
Adult HUS, which constitutes a tiny minority of all cases of HUS, tend to result from a pathogenesis different from
that of most childhood cases, and adult HUS may be relatively unresponsive to therapies effective in children.[12,
11]
Prognostic factors
Considerable interest is attached to the identification of reliable prognostic factors early in the course of HUS.
Such factors should be important in stratifying treatment groups to assess the effectiveness of various therapies.
Such factors might also permit the start of aggressive novel strategies early in the course of diseases with the
poorest prognoses.
A recent review of 387 children with HUS greatly contributed to this important objective.[14]
About 60% of 276 subjects tested had Stx-E coli –related HUS. The age at onset, leukocyte count, and
evidence of CNS involvement did not help in predicting the time to recovery.
The combined absence of prodromal diarrhea and/or of Stx toxin in stool was associated with worsened
outcome. Only 34% of individuals who lacked both features recovered normal renal function, as compared
with 65-76% of those who had 1 or both features.
For 118 patients followed up after postdiarrheal HUS with kidney transplantation, the recurrence rate was
0.8%; recurrence caused graft loss in a single patient.
Stx-E coli –related HUS had the lowest risk for graft loss of any HUS associated with end-stage renal
disease.
For 63 patients with nondiarrheal HUS who had a kidney transplant without factor H deficiency, 21% had
recurrence with graft loss.
Nearly 30% of 7 transplanted nondiarrheal cases with factor H gene mutations recurred.
In transplanted cases without factor H deficiency or genetic defect, low C3 levels may enhance risk for recurrence
with graft loss.
Tacrolimus-associated HUS improves in only 45% of patients despite their receiving various combinations of
treatment, including anticoagulation, antiplatelet therapy, dialysis, or plasma exchange, even when tacrolimus is
replaced with cyclosporine.
Graft loss occurs in 25% of such cases and even in cases that receive a new allograft, HUS-related death occurs
in approximately one third. If associated liver failure is present, 60% die.[56]
As disappointing as the various statistics might be, they are better than the recurrence risk for heritable adult
HUS, which is about 60% for both autosomal recessive and autosomal dominant forms .
In nonindustrialized nations, dysentery due to S dysenteriae distinctly worsens the patient's prognosis for ensuing
HUS. However, in industrialized nations, HUS occurring after a respiratory prodrome (which is often due to
Diplococcus pneumoniae infection) distinctly worsens the prognosis.
Patient Education
Education about risks associated with exposure to Stx-elaborating infectious agents, such as E coli or S dysenteriae should
reduce the risk for postinfectious HUS.
Contributor Information and Disclosures
Author
Robert Stanley Rust, Jr, MD, MA Thomas E Worrell Jr Professor of Epileptology and Neurology, Co-Director of FE Dreifuss
Child Neurology and Epilepsy Clinics, Director, Child Neurology, University of Virginia School of Medicine; Chair-Elect, Child
Neurology Section, American Academy of Neurology
Robert Stanley Rust, Jr, MD, MA is a member of the following medical societies: Child Neurology Society, Society for Pediatric
Research, American Headache Society, International Child Neurology Association, American Academy of Neurology, American
Epilepsy Society, American Neurological Association
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.
Nestor Galvez-Jimenez, MD, MSc, MHA The Pauline M Braathen Endowed Chair in Neurology, Chairman, Department of
Neurology, Program Director, Movement Disorders, Department of Neurology, Division of Medicine, Cleveland Clinic Florida
Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical societies: American Academy of Neurology,
American College of Physicians, International Parkinson and Movement Disorder Society
Chief Editor
Amy Kao, MD Attending Neurologist, Children's National Medical Center
Amy Kao, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society,
Child Neurology Society
Disclosure: Have stock (managed by a financial services company) in healthcare companies including AbbVie, Allergan,
Celgene, Cellectar Biosciences, Danaher Corp, Mckesson.
Additional Contributors
David A Griesemer, MD Professor, Departments of Neuroscience and Pediatrics, Medical University of South Carolina
David A Griesemer, MD is a member of the following medical societies: American Academy for Cerebral Palsy and
Developmental Medicine, Society for Neuroscience, American Academy of Neurology, American Epilepsy Society, Child
Neurology Society
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2/25/2019 https://emedicine.medscape.

Hemolytic Uremic Syndrome

Hereditary, recurrent TTP - Idiopathic or ADAMTS-13 deficient

Postinfectious TTP - Acquired, anti-ADAMTS-13 immunoglobulin G (IgG)–mediated

TTP-like illness without identifiable ADAMTS-13 deficiency

Postinfectious HUS - Stx-related (IStx-HUS)

Postinfectious HUS - Non–Stx-related (INon-Stx HUS)

Sporadic or immunologic HUS - Diarrheal and nondiarrheal

Familial HUS - H-factor normal or H-factor deficient

TMA not otherwise specified

Stx-related postinfectious HUS, or IStx-HUS

See the list below:

HUS due to this agent has a distinct midsummer seasonal predilection.

Vomiting occurs in 30-60% of patients.

Dysentery due to S dysenteriae or Yersinia organisms may be severe.

Patients may have a history of severe fever.

HIV infection or AIDS

Systemic lupus erythematosus (SLE)

Antiphospholipid antibody syndrome

Bone marrow or stem cell transplantation

Immunosuppression with cyclosporin, tacrolimus, or methylprednisolone (Tacrolimus-associated disease is usually

Pancreatic cancer treated with gemcitabine

Cancer treated with mitomycin or other chemotherapy drugs

Diethylene glycol exposure

Pregnancy or use of oral contraceptives

Fever may be present.

Postinfectious HUS with diarrheal prodrome may produce abdominal tenderness.

Colonic ischemia may be severe enough to represent a surgical emergency.

Abdominal tenderness is occasionally due to the development of pancreatitis.

Endocrine causes include pregnancy and use of oral contraceptives.

Neurological Manifestations of Uremic Encephalopathy

Neurological Sequelae of Infectious Endocarditis

Primary CNS Lymphoma

Systemic Lupus Erythematosus (SLE)

Thrombotic Thrombocytopenic Purpura (TTP)

Severe HUS GI bleeding is associated with consumptive thrombocytopenia.

Platelet survival time is shortened in HUS.

Platelet counts may be < 80 X 109/L (< 80,000/mm3).

Additional findings include the following:

Microangiopathic changes occur in RBCs.

Leukocytosis may be found.

Because hemolytic anemia is nonimmune, results of Coombs testing is negative.

Fibrinogen levels may be normal or increased.

Evidence of inflammatory changes may be found in blood and urine.

Culture and other findings

Associated bacteremia is not uncommon.

Stx may be identified in stool in postinfectious HUS with diarrheal prodrome.

Hypercalcemia is common in HUS.

Diethylene glycol intoxication

Use of anticancer drugs (eg, cisplatin, mitomycin, bleomycin, gemcitabine)

Use of immunomodulatory drugs (eg, cyclosporine, quinidine, interferon, tacrolimus, OKT3)

Increased brightness of the kidney may be detected on renal ultrasonography.

Subdural effusions may be observed.

These changes apparently develop early in the course of illness.

Management of blood pressure

Other medical therapies

Anticonvulsant therapy may be required to control seizures.

Further Outpatient Care

Infants and children

HUS-associated renal failure usually persists for several weeks.

About 30-50% of patients require dialysis, which indicates a worsened prognosis.[13]

Contributor Information and Disclosures

Disclosure: Nothing to disclose.