Hemolytic Uremic Syndrome Revisited Shiga Toxin, Factor H, and Fibrin Generation

Transcription

Pathology Patterns Reviews
Hemolytic Uremic Syndrome Revisited
Shiga Toxin, Factor H, and Fibrin Generation
Douglas P. Blackall, MD,1 and Marisa B. Marques, MD2
Key Words: Factor H; HUS; Hemolytic-uremic syndrome; Microangiopathic hemolytic anemia; Renal failure; Shiga toxin; Thrombotic
microangiopathy
DOI: 10.1309/06W402EHNGVVB24C
Abstract
The hemolytic uremic syndrome (HUS) is a disease
characterized by microangiopathic hemolytic anemia,
thrombocytopenia, and renal failure. These features
reflect the underlying histopathologic lesion: fibrin-rich
thrombi that predominate in the renal microvasculature.
HUS most commonly affects children younger than 5
years and is associated with Shiga toxin–producing
enteric bacteria, the most important of which is
Escherichia coli O157:H7. In this setting, HUS is
epidemic and also might affect adults, particularly
elderly people. Sporadic cases of HUS more commonly
occur in adults and are associated with a wide variety
of inciting agents and conditions. Although the disease
manifestations might be similar and endothelial activation or injury likely represents a common etiologic
event, differing responses to therapy suggest different
pathogenic mechanisms. As more is understood about
the underlying pathogenesis of the diseases that we now
lump together as HUS, more efficacious and rational
treatment and prevention strategies are likely to follow.
© American Society for Clinical Pathology
The hemolytic uremic syndrome (HUS) is a disease
characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. It was first described by
Gasser et al in 1955 and is the most common cause of renal
failure in early childhood.1,2 However, all age groups are
affected by this disease process, and extrarenal manifestations of the disease may occur (eg, microthrombi in the
brain).2 Vascular endothelial injury seems to have a central
role in HUS pathogenesis, with resulting fibrin-rich thrombi
responsible for the clinical manifestations of the disease.3
Hemolysis occurs as erythrocytes traverse occluded vessels,
with schistocytes typically abundant on examination of the
peripheral blood smear. Platelets are consumed at sites of
vascular injury, resulting in thrombocytopenia. Finally, for
reasons that are not completely understood, thrombus formation is most significant and obvious in the kidneys, with
resulting renal failure.
The clinical manifestations of HUS can be difficult to
distinguish from thrombotic thrombocytopenic purpura (TTP).
In fact, many have viewed these disorders as an overlap
syndrome (TTP-HUS), with the predominant clinical manifestation determining the ascribed diagnosis. 4 Thrombotic
microangiopathies with predominant neurologic manifestations
might be diagnosed as TTP, while those with primary renal
involvement are named HUS. However, the past decade has
realized an explosion in our understanding of the pathogenic
underpinnings of both illnesses, to the extent that it is becoming
possible to differentiate at least 2 distinctive pathologic
processes. This is an important consideration because therapy
for each is quite distinct. This review focuses on the clinical
manifestations of HUS, its laboratory findings and pathogenesis, and the implications for therapy that have resulted from a
greater understanding of the disease and its causes.
Am J Clin Pathol 2004;121(Suppl 1):S81-S88
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Blackall and Marques / HEMOLYTIC UREMIC SYNDROME REVIEW
Case Study
A previously healthy 4-year-old girl was admitted to the
hospital with a 1-week history of abdominal pain and watery
diarrhea. Just before admission, bloody diarrhea was noted.
The patient was admitted with a presumptive diagnosis of
gastroenteritis and dehydration. Blood and stool cultures were
obtained, and the patient was hydrated. Admitting laboratory
data were all within defined reference ranges, including a
hemoglobin of 12.9 g/dL (129 g/L; reference range, 11.5-13.5
g/dL [115-135 g/L]), a hematocrit of 37.4% (0.37; reference
range, 34.0%-40.0% [0.34-0.40]), a platelet count of 306 ×
103/µL (306 × 109/L; reference range, 150-400 × 103/µL
[150-400 × 109/L]), and a creatinine level of 0.4 mg/dL (35
µmol/L; reference range, 0.1-0.7mg/dL [9-62 µmol/L]).
A few days after admission, the patient’s laboratory
values began to change: her hemoglobin, hematocrit, and
platelet count fell, and her creatinine level rose. At this time,
the microbiology laboratory reported a negative blood
culture, but a stool culture was positive for Escherichia coli,
serotype O157:H7. An enzyme immunoassay also was positive for Shiga toxin. One week after the onset of the patient’s
bloody diarrhea, her hemoglobin had fallen to 6.9 g/dL (69
g/L), her hematocrit was 19.5% (0.20), her platelet count
was 39 × 103/µL (39 × 109/L), and her creatinine level had
risen to 4.9 mg/dL (433 µmol/L). She was also anuric, for
which hemodialysis was started. During the next few days,
the patient received supportive care and a total of 3 dialysis
procedures. Almost immediately, her condition improved as
evidenced by a falling creatinine level, a rising platelet count,
and stabilized hemoglobin and hematocrit values (although
the patient required 1 transfusion of packed RBCs). After a
2-week hospitalization, the patient’s creatinine level and
platelet count returned to normal, and she was discharged
from the hospital.
Clinical Manifestations
The preceding case study represents the classic manifestations of HUS. The most common form of the syndrome is
associated with a prodromal diarrhea (D+ HUS) that occurs
in healthy young children between 6 months and 5 years of
age.1 Initially, the diarrhea is watery but usually evolves to a
hemorrhagic colitis. This is followed by evidence of hemolysis (falling hemoglobin and hematocrit values; schistocytes
on peripheral blood smear) and thrombocytopenia within 5
to 7 days. Oliguria and anuria may follow several days later.
Therapy is largely symptomatic, and the outcome for
patients with D+ HUS generally is favorable, although the
combined mortality rate and rate of end-stage renal disease is
approximately 10%.5 In addition, long-term follow-up of
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survivors has demonstrated that 25% will have renal
dysfunction (as characterized by a glomerular filtration rate
lower than 80 mL/min per 1.73 m 2 ), hypertension, or
proteinuria.5 Fortunately, recurrence is uncommon.
In contrast with diarrhea-associated HUS, the sporadic,
nonprodromal form of HUS is not associated with a
preceding diarrhea (D– HUS) and is rare in childhood. This
form of HUS has a worse prognosis, is more likely to
relapse, and sometimes is associated with a family history of
disease.2 In addition, D– HUS is associated with certain
drugs (eg, pentostatin, cyclosporine, mitomycin C), various
malignant neoplasms (eg, pancreatic and lung cancers), solid
organ and bone marrow transplantation, and vasculitic
diseases.2 D– HUS is associated with a greater incidence of
extrarenal disease (eg, neurologic complications, liver
dysfunction, pancreatic and cardiac problems) and might be
difficult to distinguish from TTP. Still, the hallmarks of HUS
remain the same: microangiopathic hemolytic anemia,
thrombocytopenia, and renal failure.
Laboratory Findings
HUS is largely a clinical diagnosis supported by laboratory abnormalities that reflect the underlying pathophysiologic process (intravascular fibrin-rich thrombus formation).
A nonimmune, schistocytic, hemolytic anemia with prominent polychromatophilia is seen on the blood smear.
Biochemical evidence supporting hemolysis also is routinely
present, including an elevated lactate dehydrogenase level, a
low serum haptoglobin concentration, and an unconjugated
hyperbilirubinemia. Thrombocytopenia is a common finding
in HUS and directly reflects the underlying pathophysiology
(endothelial injury and platelet consumption). However,
severe thrombocytopenia (<10 × 103/µL [<10 × 109/L]) is
rare, with most patients having platelet counts in the 50 ×
103/µL (50 × 109/L) range.1 Neither the severity nor the duration of thrombocytopenia correlates with overall disease
severity or likelihood of long-term renal sequelae.2 However,
persistent renal disease (decreased glomerular filtration rate,
hypertension, proteinuria) after apparent renal recovery
seems to be associated with the development of end-stage
renal disease (10%-15% of patients with HUS).5 Therefore,
extended follow-up is recommended for all patients.
The results of routine coagulation studies (prothrombin
time, partial thromboplastin time, fibrinogen) usually are
normal in HUS, with only mildly elevated fibrin degradation
product levels. However, a recently published study of children with E coli O157:H7 infections, in whom HUS subsequently developed, demonstrated prothrombotic coagulation
abnormalities preceding clinical evidence of the syndrome.6
The authors found that these patients, in comparison with
infected children in whom HUS did not develop, had significantly higher median plasma concentrations of prothrombin
fragment 1+2, tissue plasminogen activator antigen, tissue
plasminogen activator inhibitor type 1 complex, and D-dimer
levels. They also found that urinary concentrations of β2microglobulin and N-acetyl-β-glucosaminidase (early
markers of renal injury) were not elevated until the obvious
clinical onset of HUS. This implies that the tubular injury
and renal insufficiency accompanying HUS result primarily
from the formation of fibrin thrombi (rather than the direct
toxic effect of circulating bacterial products such as Shiga
toxin). Finally, in contrast with patients with TTP, patients
with D+ HUS almost invariably do not have deficiencies of
von Willebrand factor–cleaving protease (ADAMTS 13), a
metalloproteinase important in the pathogenesis of TTP.7
However, this protease is much more likely to be deficient in
children and adults with atypical, D– HUS and might define
a true overlap syndrome with TTP.7,8
HUS is a thrombotic microangiopathy confirmed by
histopathologic examination. Endothelial injury is evident
(glomerular endothelial cell swelling), and thrombotic occlusion of the glomerular capillary lumen results in ischemic
tissue damage.3 Tubular epithelial cell injury, mesangial
expansion, and mesangiolysis also have been observed. In
the most severe cases, cortical necrosis is seen. In addition to
these changes, inflammatory cells (neutrophils and
macrophages) infiltrate the kidneys, and apoptosis of renal
cortical glomerular and tubular cells has been documented.3
The thrombotic microangiopathic changes of D+ HUS also
can be seen in other organ systems (eg, the central nervous
system). In contrast with the aforementioned findings, the
microangiopathic changes of TTP and D– HUS are similar.
They are arteriolar, and the associated thrombi are rich in
platelets and von Willebrand factor rather than fibrin.9 These
findings suggest that TTP/D– HUS cases have a pathogenesis that is different from that of D+ HUS.
Pathogenesis
D+ Hemolytic Uremic Syndrome
Epidemic and endemic D+ HUS is associated with
infections caused by verocytotoxin (Shiga toxin)–producing
organisms, including E coli O157:H7, E coli O26:H11, and
Shigella dysenteriae type 1.1 In North America and Western
Europe, infection with E coli O157:H7 is the predominant
cause of HUS.3 Food and water are the most common modes
of infection, although person-to-person transmission has
been described.10 After a mean incubation period of 3 days,
infected patients develop a watery diarrhea with cramping
abdominal pain that may evolve into hemorrhagic colitis. A
week after the onset of diarrhea, HUS will develop in 15% of
patients.6 Shiga toxins (Stx 1 and Stx 2) are considered the
major virulence factors of the organisms involved in HUS.
However, a wide variety of other elaborated bacterial products, including lipopolysaccharide (LPS) and the adhesins—
intimin and E coli–secreted proteins A, B, and D—also
might have important pathogenic roles.3 In addition, the host
inflammatory response to infection and a prothrombotic state
might contribute to the development of HUS.11,12
As previously mentioned, Shiga toxins seem to be the
major virulence factor responsible for the pathogenesis of
HUS. This is highlighted by the fact that enteropathogenic
strains of E coli, although they possess many of the same
virulence factors as enterohemorrhagic strains (eg,
O157:H7), have never been associated with HUS, presumably because they do not elaborate Shiga toxin.3 Human
isolates of Shiga toxin–producing E coli express Stx 1 or Stx
2 encoded on a bacteriophage. These toxins are 60% homologous, but Stx 1 from E coli is identical to the toxin
produced by S dysenteriae, except for a single amino acid
substitution.3 Stx 2 seems to be more virulent than Stx 1 with
respect to the development of hemorrhagic colitis and
HUS.13-15 Experimental data also support this clinical observation, as Stx 2 is 400 times more potent than Stx 1 in
mice. 16 In addition, human intestinal and glomerular
endothelial cells are more sensitive to the in vitro cytotoxic
effects of Stx 2.17,18
Although Shiga toxin virulence is not understood
completely, its biochemistry, cell biology, and molecular
effects have been well studied. Shiga toxin is a holotoxin
containing 1 A subunit and 5 B subunits.3 The B subunit is
responsible for toxin binding and has specificity for the
glycosphingolipid membrane receptor globotriaosylceramide
(Gb3).3 This molecule is the biochemical equivalent of the Pk
blood group antigen. 19 Gb3 facilitates endocytosis and
translocation into intestinal epithelial cells. The A subunit
has N-glycosidase activity and contributes to cell death by
inhibiting protein synthesis at the level of 28S ribosomal
RNA. 3 A toxic effect on both intestinal epithelial and
endothelial cells might facilitate access of the toxin to the
bloodstream with subsequent systemic pathologic effects.
This is important in HUS pathogenesis because there is no
evidence for bacteremia in human disease except for 2
isolated case reports.20,21
After gaining access to the circulation, there is evidence
that the toxin is transported to distant sites through an interaction with neutrophils, monocytes, and platelets.3,22 Once in
the circulation, the toxin binds vascular endothelial cells rich
in Gb3. Each B subunit binds with high affinity to terminal
galactose α1,4β galactose disaccharides in Gb3 membrane
receptors.11 Glomerular, colonic, and cerebral endothelial
cells are rich in Gb3 receptors, as are renal mesangial and
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tubular epithelial cells.11 This might account for the localization of tissue damage in HUS (ie, renal predominant).
Shiga toxin induces a wide variety of effects that are
directly related to the toxin but also result from the host
inflammatory response to the toxin and toxin-induced injury.
The direct toxic effect results primarily from an inhibition of
protein synthesis.3 Stx subunit A undergoes partial proteolysis and disulfide bond reduction in kidney cells. These
processes generate an enzyme (N-glycosidase) that cleaves
an adenine from 28S ribosomal RNA and inhibits the elongation of peptide chains. In so doing, protein synthesis is
disrupted and cell death ensues. Stx also has been shown to
induce apoptosis in endothelial cells and in renal tubular and
intestinal epithelial cells, both in vitro and in vivo.3,23,24 In
addition, Stx has been shown to up-regulate a number of
transcription factors in human vascular endothelial cells that
belong to the tumor necrosis factor (TNF)-stress-related
signaling pathway and the NFκB pathway.3 These transcription factors have important roles in apoptosis and in immune
regulation, cell proliferation, and the regulation of proinflammatory cytokines.
Recent evidence strongly suggests that Shiga toxin
works in concert with other agents to induce HUS and upregulates the expression of additional factors that might have
important roles in HUS pathogenesis.3 For example, animal
models (mouse, rabbit, baboon) indicate that LPS might be
involved in the pathogenesis of HUS.25 In baboons, the
previous administration of LPS can prime animals to develop
severe HUS following the administration of otherwise
subtoxic doses of Shiga toxin.26 Similarly, pretreatment of
rabbits and mice with Stx enhanced the lethal effects of
LPS.25 This same synergistic effect also has been demonstrated in vitro using human vascular endothelial cells.27 In
humans, however, the pathophysiologic role of LPS and
HUS is less clear, because endotoxemia has not been demonstrated in patients with E coli–associated HUS.3 However,
there is at least indirect evidence that LPS enters the human
circulation and participates in HUS pathogenesis, because
antibodies to LPS can be demonstrated in up to 90% of
patients with Stx-mediated HUS.28
Regardless of the role of LPS in HUS, it is becoming
clear that a variety of proinflammatory and procoagulant
mediators might be important causes of tissue injury in HUS.
Children with D+ HUS have increased circulating levels of
granulocyte colony-stimulating factor, TNF-α, interleukin
(IL)-1β, IL-6, IL-8, and monocyte chemoattractant protein1.3,12 Although these findings do not prove that elevated
levels of inflammatory mediators have a pathogenic role in
HUS, they indicate a marked host inflammatory response.
Shiga toxins might be responsible for up-regulating the
genes that give rise to these mediators and might provoke the
direct release of these mediators from the cells to which
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Shiga toxins bind (eg, colonic epithelial cells and multiple
cell types in the kidney).
In addition to recruiting inflammatory cells (neutrophils)
to tissue sites that have experienced Shiga toxin–induced
injury, it has been shown that certain cytokines (TNF-α, IL6, and IL-8) up-regulate the expression of Gb3 on renal
endothelial cells, potentially promoting further Shiga toxin
binding and subsequent injury.11,29 A recent study also
showed that Shiga toxin induces expression of P-selectin and
intercellular adhesion molecule-1 on human umbilical vein
endothelial cells.12 These adhesion molecules are important
in tethering circulating leukocytes to endothelium before
extravasation to sites of tissue injury. Interestingly, this study
demonstrated adhesion molecule up-regulation in response
to Stx 2 but not to Stx 1. This might represent at least 1
reason for the well-established fact that systemic complications more often occur with Stx 2–producing strains of
enterohemorrhagic E coli than with Stx 1 producers.
There is growing evidence that Shiga toxin, either
directly or through the elaboration of a mediator, might
induce a prothrombotic state in patients with HUS. Stx 1,
through its B (binding) subunit, binds Gb3 receptors on
platelets, with subsequent internalization of the toxin and
platelet activation.22 Stx 1 also has been shown to increase
fibrinogen binding to platelets, which might further promote
the development of the platelet-fibrin thrombi found in
HUS.22 Stx 1 also induced the binding of platelets to human
vascular endothelial cells pretreated with TNF-α.30 Through
a direct toxic effect on the endothelium, Shiga toxin might
expose the subendothelium, which contains collagen and von
Willebrand factor. This would further enhance platelet adhesion, platelet aggregation, and fibrin formation (through the
local exposure of tissue factor and resultant downstream
effects). Thus, it is easy to see how Shiga toxin could directly
contribute to thrombosis via endothelial injury and platelet
activation. However, it is also important to note that patients
with E coli infections in whom HUS ultimately develops
might have prothrombotic coagulation abnormalities that
precede a clinical diagnosis of HUS, when the hematocrit,
platelet count, and serum creatinine concentration are
normal.6 At this point, the mechanism for this prothrombotic
state has not been elucidated but might represent a target to
prevent the progression of HUS in patients with diagnosed
Shiga toxin–associated enteric infections.
D– Hemolytic Uremic Syndrome
Non–Shiga toxin–associated, D– HUS accounts for 95%
of all cases of HUS that occur in adults.2 Unlike the more
common childhood form of the disease, D– HUS is associated with a higher mortality rate, a higher rate of treatment
failure and relapse, and a high rate of progression to endstage renal disease (50%-100% depending on the case
series).1,2 In addition, patients with atypical D– HUS who
receive a renal transplant have a very high rate of disease
recurrence, in some series close to 100%. 31 This is in
contrast with children with end-stage renal disease secondary
to D+ HUS: the rate of HUS recurrence is extremely rare.
All of these differences suggest that the underlying pathogenesis of D+ and D– HUS is different. At the same time, it
is clear that activation of microvascular endothelium has a
central role in HUS irrespective of the underlying cause of
disease. Furthermore, the clinical disease is essentially indistinguishable: microangiopathic hemolytic anemia, thrombocytopenia, and renal failure.
Non–Shiga toxin–associated, D– HUS can be sporadic
and idiopathic or familial and relapsing or occur secondary to
a wide variety of conditions, including pregnancy (postpartum
HUS), HIV infection, autoimmune disorders (antiphospholipid syndrome, systemic lupus erythematosus, scleroderma),
cancer, and transplantation (hematopoietic progenitor cell and
solid organ).2 Certain drugs also have been associated with the
development of HUS, particularly in transplant recipients (eg,
cyclosporine A, tacrolimus, methotrexate).31 In general, the
pathogenesis of D– HUS is not well understood and has not
been studied extensively. The one exception is cases that are
familial and relapsing. These cases are highly associated with
mutations in a complement regulatory protein termed factor
H.32 Of all cases of atypical D– HUS, 10% to 30% are associated with factor H mutations; consequently, the term factor
H–associated HUS has been coined.33
Factor H is a 150-kd multifunctional plasma glycoprotein that has a pivotal role in regulating the alternative
pathway of complement activation.32 It acts as a cofactor for
factor I in the degradation of newly formed C3b molecules
and exhibits decay-accelerating activity in controlling the
formation and stability of C3 convertase (C3bBb). The
secreted plasma protein is organized into 20 homologous
units termed short consensus repeats. In addition to its role as
a complement regulatory protein, factor H has anti-inflammatory properties, is a ligand for a number of plasma
proteins (C-reactive protein, adrenomedullin, osteopontin),
and binds extracellular matrix proteins. Detailed structurefunction studies have defined 3 distinct binding regions for
the ligands: C3b, glycosaminoglycans, and heparin.34
A deficiency of functional factor H in plasma is associated with recurrent microbial infections, membranoproliferative glomerulonephritis type II (MPGN II) and HUS. 32
Recent evidence strongly suggests that factor H mutations
are associated with atypical D– HUS and that these mutations are almost entirely restricted to short consensus repeat
20, a “hot spot” for the disease process.32 These gene mutations have been identified in sporadic and familial cases of
HUS. It is not completely clear how deficiencies of factor H
result in disease, but it is known that in MPGN II, both factor
H alleles are inactivated and that the protein is absent from
the plasma.35 In contrast, in atypical HUS, suboptimal factor
H activity is the result of 1 intact and 1 defective allele.32
Thus, it seems that the local level of factor H is highly relevant to the manifest disease process.
In MPGN II, the glomerular membrane is damaged
owing to the absence of endogenous complement regulators,
and there is no plasma factor H to serve this function. In
atypical HUS, suboptimal factor H activity is sufficient to
maintain the integrity of the glomerular and subendothelial
membranes under normal conditions. However, upon insult
(any of the conditions associated with D– HUS), endothelial
cells are injured, complement is activated, and there is insufficient factor H to dampen down the local inflammatory
response. Thus, the activity of factor H becomes pivotal in
determining the balance between tissue repair and tissue
damage. Although the specific mechanisms that give rise to
factor H–associated HUS are unknown, knowledge of this
factor in HUS pathogenesis might serve as a springboard for
the development of rational approaches to therapy.
Treatment
Standard therapy for Shiga toxin–associated HUS is
primarily supportive and designed to reverse renal failure
and control hypertension (as it occurs).1 Peritoneal dialysis
or hemodialysis should be considered when fluid and electrolyte imbalances cannot be corrected by conservative
measures or when fluid overload compromises cardiac function. As a general principle, when the serum urea nitrogen
level exceeds 100 mg/dL (35.7 mmol/L), dialysis should be
considered, even in the absence of fluid and electrolyte
imbalances. Hypertension should be treated (eg, short-acting
calcium channel blockers, angiotensin-converting enzyme
inhibitors) to prevent congestive heart failure and
encephalopathy. Nonstandard therapies for HUS include
antiplatelet agents, anticoagulants, thrombolytic agents,
prostacyclin, intravenous immune globulin, and corticosteroids.2 To date, these therapies have not proven beneficial.
There is a limited role for transfusion medicine intervention in cases of D+ HUS. RBC transfusion might be necessary for patients with more severe hemolysis and symptomatic anemia. Platelet transfusion typically is not indicated
because these patients generally do not have a generalized
bleeding diathesis. In addition, there is at least a theoretical
risk that platelet transfusion could contribute to enhanced
microthrombosis. Platelet transfusions are best reserved for
thrombocytopenic patients who have demonstrable bleeding
or who must have an invasive surgical procedure (eg,
catheter placement for hemodialysis or peritoneal dialysis).
Finally, unlike TTP, there does not seem to be a role for
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plasma exchange in the treatment of children with D+ HUS,
although it is important to note that there has not been a
controlled prospective study in this patient population. In
contrast, there is at least suggestive evidence that therapeutic
plasma exchange might be of benefit to elderly patients with
D+ HUS.36 These patients tend to have disease with more
significant extrarenal (ie, neurologic) manifestations, and
there is a high overall mortality. In such patients, plasma
exchange might represent a rational therapeutic approach.
On the research front, there has been interest in determining whether a Shiga toxin binding agent could favorably
affect the course and outcome of D+ HUS. A recent report
described the use of orally administered silicon particles
linked to the Gb3 molecule, the receptor for Shiga toxin.37 The
rationale for this study was that intestinal absorption of Shiga
toxin does not occur as a one-time event but, rather, continues
after the onset of HUS. Binding and elimination of elaborated
Shiga toxin could have a beneficial effect. Unfortunately, this
did not seem to be the case. It simply might be that there is
little free Shiga toxin available owing to the tight binding of E
coli to the intestinal epithelial surface. Alternatively, it might
be that once HUS becomes evident, the underlying disease
process (and the related host response) is too advanced to be
altered by simply removing the inciting agent (Shiga toxin). It
might be that an orally administered Shiga toxin binding agent
would have greatest benefit in preventing the progression to
HUS in patients with documented Shiga toxin–associated
enteric infections, but such a study has not been reported.
The optimal management for patients with D– HUS is
much less clear than that for patients with Shiga toxin–associated disease. Patients with D– HUS represent a heterogeneous population, from the standpoint of inciting etiologic
agent and, possibly, pathogenesis. These patients have significantly higher chronic morbidity (eg, end-stage renal disease)
and mortality in comparison with patients with D+ HUS.
Historically, patients with D– HUS have been treated with
intensive therapeutic plasma exchange; however, relapse
rates are high, and this therapy is of unproven benefit in
preventing chronic renal failure.2 Unfortunately, and as
previously mentioned, patients with D– HUS who receive
renal transplants also have a very high rate of disease relapse
with subsequent loss of the transplanted organ.31 Plasma
therapy (infusion or exchange) would seem to be a rational
therapeutic approach in the subset of patients with D– HUS
found to have a factor H abnormality. However, there are no
controlled studies that provide proof for this therapy.
Prevention and New Horizons
It is clear that the best way to prevent D+ HUS is
to prevent primary infection with Shiga toxin–producing
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organisms capable of causing the disease. This is a pressing
and important public health concern. Just as clear is the fact
that D– HUS prevention strategies will not likely be forthcoming until more is known about the pathogenesis of these
heterogeneous disorders. Thus, this discussion will be
limited to interventions to prevent D+ HUS.
In patients who already are infected with Shiga
toxin–producing bacteria, a number of strategies have been
studied to prevent the development of HUS (known to occur
in about 15% of all who are infected). Of these, antibiotic
treatment of E coli O157:H7 infections is the best studied
and, perhaps, most controversial. 38 The rationale for
providing antibiotics to prevent HUS progression is obvious:
eliminate the bacteria that produce the disease-causing toxin.
On the other hand, there is equally valid concern that antibiotic therapy might, in fact, promote progression to HUS: (1)
Bacteria might release toxin as a result of antibiotic-induced
injury. (2) Treatment with antibiotics might give E coli
O157:H7 a selective growth advantage if these organisms are
eliminated less readily by treatment in comparison with
normal gut flora. (3) Several antimicrobial agents
(quinolones, trimethoprim, furazolidone) are potent inducers
of Shiga toxin 2 gene expression, which could increase toxin
levels in the intestine.
A number of studies have demonstrated a positive effect
or no association between antibiotic treatment of infection
and the subsequent development of HUS.38 A recent metaanalysis also demonstrated that antibiotic therapy was not
associated with HUS.39 However, a prospective cohort study
of 71 children with documented E coli O157:H7 infections
(14% of whom developed HUS) showed that in 56% of children treated with antibiotics, HUS developed, whereas it
developed in only 8% of those who were not treated.40 It
seems that a randomized trial will be required to conclusively determine whether antibiotic treatment of E coli
O157:H7 enteritis increases the risk of HUS.
In addition to antibiotics, other HUS prevention strategies are being studied, including Shiga toxin vaccines. A
recent report described the development of DNA vaccines to
prevent HUS in a murine model of the disease.41 Eukaryotic
plasmids expressing the B subunit of Stx 2 or the B and A
subunits together were evaluated for their ability to elicit in
vitro humoral responses and a protective in vivo immune
response. The B+A plasmid was most efficacious and was
potentiated when a plasmid encoding granulocytemacrophage colony-stimulating factor was coadministered.
This strategy underscores the fact that it may be possible to
prevent HUS or alter the course of established disease by
inducing a potent neutralizing humoral immune response.
This work follows other animal studies demonstrating that
either the active induction of Shiga toxin antibodies or their
passive provision can prevent or ameliorate HUS.42,43
Conclusions
The classic clinical presentation of HUS is characterized
by microangiopathic hemolytic anemia, thrombocytopenia,
and renal failure. These features reflect the underlying
histopathologic lesion: platelet-fibrin thrombi that predominate in the renal microvasculature. HUS most commonly
affects children younger than 5 years and is associated with
Shiga toxin–producing enteric bacteria, the most important
of which is E coli O157:H7. In this setting, HUS is epidemic
and also might affect adults, particularly elderly people.
Sporadic cases of HUS (D– disease) more commonly occur
in adults and are associated with a wide variety of inciting
agents and conditions. Although the disease manifestations
are similar, different pathogenic mechanisms and responses
to therapy indicate that they might represent 2 separate
diseases, with D– HUS sometimes difficult to distinguish
from TTP. As more is understood about the underlying
mechanisms giving rise to the diseases that we now lump
together as HUS, more efficacious and rational treatment and
prevention strategies are likely to follow.
From the Departments of Pathology, 1University of Arkansas for
Medical Sciences, Little Rock, and 2University of Alabama at
Birmingham.
Address reprint requests to Dr Blackall: Dept of Pathology,
Arkansas Children’s Hospital, 800 Marshall St, Slot 820, Little
Rock, AR 72202.
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Hemolytic Uremic Syndrome Revisited Shiga Toxin, Factor H, and Fibrin Generation

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