Hemolytic uremic syndrome (HUS) is the
most common cause of pediatric acute renal failure, and need for renal
replacement therapy, affecting between 0.2 and 4.28 people per 100,000
worldwide. Term “Typical HUS” commonly used by paediatricians is referred to be with
a preceding prodrome of a diarrhea (D+). Typical HUS representing >90% of
HUS cases, and mainly found in childhood. This form of HUS follows
gastrointestinal infection with enterohemorrhagic Escherichia coli (EHEC), as a
complication of the infection with Shiga toxin–producing bacteria. These patients require adequate care includes
intravascular fluid replacement to improve the perfusion of affected organs,
primarily brain, gut, and kidneys. Supportive treatment of HUS includes the
transfusion of red blood cells (PRBC) and platelets. Antibiotic therapy of EHEC
infection is unnecessary as the intestinal infection is self limiting and
non-invasive, and antibiotics might encourage bacterial release of Stx and
increase the clinical risk of HUS. Shigella related HUS requires prompt therapy
with appropriate antibiotics.
“Atypical HUS,” indicates a presentation
of HUS without preceding diarrhea (D-), is a misnomer. HUS caused by EHEC
colonisation, without an antecedent diarrhea is known, and on the other hand,
complement mediated HUS is known to be triggered by a diarrheal prodrome. It may be caused by pneumococcal pneumoniae
or HIV, complement dysregulation, drugs (quinine, calcineurin inhibitors,
chemotherapy), other pathologies (malignancy, systemic lupus erythematosus, and
antiphospholipid antibody syndrome), or, rarely, to defective cobalamin
metabolism in infants.
During the last 10 years, it has become
evident that atypical HUS is strongly associated with mutations or polymorphism
in proteins implicated for activation or regulation of the alternative pathway
of complement with the Factor H heterozygous mutations representing the major
cause of such HUS. Defects in the plasma and membrane-bound proteins such as
complement factor H (FH) and the FH related proteins (CFHRs), factor I (FI),
membrane cofactor protein (MCP, CD46), and recently thrombomodulin (THBD) play
a major role in the pathogenesis of this atypical HUS. Anti- Factor H
autoantibodies represent a significant etiology of atypical HUS (newly
discovered), mainly in preadolescent children, but may also be present in
adults. This form of HUS is frequently associated with a particular genetic
status consisting frequently of unequal recombination occurring in the CFH
family locus. Recent guidelines for initial therapy from the European Pediatric
Study Group for HUS recommend starting plasmatherapy as early as possible,
within 24 hours of presentation. This is justified by the frequent rapid
deterioration of renal function in patients with CFH, combined CFI, C3, and CFB
mutations (and the possibility of anti-CFH antibodies).
In conclusion, HUS is not a benign
disease. Even the so-called “classical” D+ HUS has substantial long-term
morbidity. The incidence of Atypical HUS is on the rise, with better
understanding of the pathogenesis of the disease. New strategies are emerging
including the exciting response shown to Eculizumab by the patients with EHEC
0104:H4 epidemic in Germany and Europe. More newer therapies are urgently
needed for this devastating disease.
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