HEMOLYTIC-UREMIC SYNDROME

HUS is a common cause of community-acquired ARF in young children.

It is characterized by the triad of microangiopathic hemolytic anemia,
thrombocytopenia, and renal insufficiency.
Et. HUS can be classified according to etiology as follows:-
Infection-induced is the most common cause of HUS; it include:
Verotoxin-producing Escherichia coli (most common, especially 057:H7
type), Shiga toxin-producing Shigella dysentereriae type 1 (common),
Neuraminidase-producing Streptococcus pneumoniae (rare), and HIV
(rare).
Genetic (Atypical) HUS include: von Willebrand factor-cleaving
protease (ADAMTS 13) deficiency, Complement factor H (or I)
deficiency/mutation, Membrane cofactor protein (MCP) mutations,
Thrombo-modulin mutations, Vitamin B12 metabolism defects, Familial
AR & AD of undefined etiology, and sporadic, recurrent, undefined
etiology without diarrhea prodrome.
Other diseases associated with microvascular injury include: SLE,
Antiphospholipid antibody syndrome, Following BM transplantation,
Malignant hypertension, Primary glomerulopathy, and HELLP syndrome.
Medication-induced include: some immunosuppressant & cytotoxic
medications, some antiplatelet agents, and quinine.
Path. Microvascular injury with endothelial cell damage is
characteristic of all forms of HUS. In each form of HUS, capillary and
arteriolar endothelial injury in the kidney particularly in glomeruli, leads
to localized thrombosis causing a direct decrease in GFR. Progressive
platelet aggregation in the areas of microvascular injury results in
consumptive thrombocytopenia. Microangiopathic hemolytic anemia
results from mechanical damage to red blood cells as they pass through
the damaged and thrombotic microvasculature.
C.M. HUS is most common in preschool and school-aged children. In
HUS caused by exotoxin-producing E. coli, onset of HUS occurs a few
day (as few as 3 days) up to 3 wk after onset of gastroenteritis with fever,

vomiting, abdominal pain, and diarrhea which is often bloody, but not
necessarily, especially early in the illness.
Following the prodromal illness, a sudden onset of pallor, irritability,
weakness, and lethargy herald the onset of HUS. Oliguria can be
present in early stages but may be masked by ongoing diarrhea. Thus,
patients can present with HUS either with significant dehydration or
volume overload. Patients can develop petechiae, but significant or severe
bleeding is rare despite very low platelet counts.
Patients with pneumococcus-associated HUS usually are ill with
pneumonia and empyema when they develop HUS. In genetic forms of
HUS, onset can be insidious when triggered by a variety of illnesses e.g.
mild, nonspecific gastroenteritis or RTI.
Inv.
CBP shows microangiopathic hemolytic anemia with schistocytes,
burr cells, and helmet cells. Coombs test is negative, with the exception
of pneumococci-induced HUS, where it is usually positive.
Thrombocytopenia is an invariable finding in the acute phase, but can
return to normal in the late stage of disease. Leukocytosis is present. PT
& PTT are usually normal.
RFT: Renal insufficiency can vary from mild elevations in serum
BUN and creatinine to ARF. GUE typically shows microscopic
hematuria and low-grade proteinuria. Renal biopsy is rarely indicated
because it carry a significant risks during active phase of the disease &
the Dx can be made on the above criteria.

prodrome. The presence or absence of toxigenic, enteropathic organisms

on stool culture has little role in making the Dx because only a minority
of patients infected with these organisms develops HUS, and the
organisms that cause HUS may be rapidly cleared during the illness,
therefore stool culture may be negative.

evaluation for the genetic forms of HUS should be considered, because

these patients are at risk for recurrence, have a severe prognosis, and can
require different therapies.

D.Dx. Thrombotic Thrombocytopenic Purpura (TTP) also is

characterized by the same features of HUS (some investigators consider
HUS and TTP to be part of a continuum of disease); however TTP may
have a more gradual onset than HUS with more CNS involvement and
fever as well as only a few cases follow the "diarrhea prodrome".
Other causes of ARF associated with a microangiopathic hemolytic
anemia and thrombocytopenia include: SLE, malignant hypertension, and
bilateral renal vein thrombosis.
Cx. HUS can be relatively mild or can progress to a severe, and even
fatal,
multisystem disease. Leukocytosis and severe prodromal enteritis herald
a severe course, but no presenting features reliably predict the severity of
HUS in any given patient.
The combination of rapidly developing renal failure and severe
hemolysis can result in life-threatening hyperkalemia.
Volume overload, hypertension, and severe anemia can all develop
soon after onset and together can precipitate heart failure.
Direct cardiac involvement is rare, but pericarditis, myocardial
dysfunction, or arrhythmias can occur.
The majority of patients with HUS have some but mild CNS
involvement e.g. irritability, lethargy, and nonspecific encephalopathy.
Severe CNS involvement occurs in ≤20% e.g. seizures & significant
encephalopathy due to focal ischemia secondary to microvascular CNS
thrombosis.
Intestinal Cxs can be protean including severe inflammatory colitis,
ischemic enteritis, bowel perforation, intussusception, and pancreatitis.
Rx. The primary approach that has substantially improved acute
outcome in HUS is the early recognition of disease, monitoring for
potential complications, and meticulous supportive care which includes:-
Careful management of fluid and electrolytes e.g. correction of
volume deficit, control of hypertension, and early institution of dialysis if
the patient becomes anuric or significantly oliguric.
Red cell transfusions are usually required because hemolysis can be
brisk and recurrent until the active phase of the disease has resolved. In
pneumococci-associated HUS, it is recommended that any administered
red cells should be washed before transfusion to remove residual
plasma, because endogenous IgM directed against the revealed T antigen
can play a pathogenic role.
Platelets generally should not be administered, regardless of platelet
count because they are almost immediately consumed by the active
coagulation and can theoretically worsen the clinical course.
lants, antiplatelets, and fibrinolytic therapy are
contraindicated because they increase the risk of serious hemorrhage.
Antibiotic therapy to clear the toxigenic organisms can result in
increased toxin release, potentially exacerbating the disease, and therefore
is not recommended, but prompt treatment of any underlying
pneumococcal infection is important.
 Plasma therapy can be of substantial benefit to patients with
identified deficits of ADAMTS 13 or factor H. It may also be considered
in patients with other genetic forms of HUS e.g. Familial undefined
etiology or sporadic but recurrent HUS.
Eculizumab (anti-C5 antibody) that inhibits complement activation is
a novel therapy for atypical familial HUS.
Pg. The mortality rate for diarrhea-associated HUS after careful
supportive care has declined to <5%. Half of the patients require dialysis
support during the acute phase of the disease. Most recover renal function
completely, but of surviving patients, 5% remain dependent on dialysis,
and up to 20-30% are left with some level of chronic renal insufficiency,
these patients require careful follow-up.
The prognosis for HUS that not associated with diarrhea is more
severe. Pneumococci-associated HUS causes increased patient morbidity,
with mortality reported ≈20%. The familial, genetic forms of HUS can be
insidiously progressive or relapsing diseases and have a poor prognosis.