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Haemolytic Uremic Syndrome (HUS)
Background
• A clinical syndrome
Characterized by:• Renal failure• Miroangiopathic hemolytic anemia• Thrombocytopenia
• Most common cause of acute renal failure in children and is increasingly recognized in adults.
• First described by Gasser et al in 1955.
Two main categories of HUS
• Shiga-like toxin associated HUS (Stx-HUS)
• Non-shiga-like toxin associated HUS(non-Stx-HUS)
• Stx-HUS: (tHUS)D+ HUSD- HUS
• Non-StxHUS: (aHUS)SporadicFamilial
Stx-associated HUS
In developed countries: • Escherichia coli serotype O157:H7 (EHEC)
most common.
In developing countries:• Shigella dysenteriae serotype 1.
Source of infection
• Human feco-oral transmission.• Milk and animal products (incompletely
cooked)• Veges, salads,drinking water contaminated by
bacteria shed in animal wastes.
Pathogenesis
• Damage to endothelial cells is the primary event.
• Cardinal lesion composed of arterial and capillary microthrombi (thrombotic microangiopathy) and red blood cell fragmentation.
Histopathological hallmark of HUS
• Thrombotic microangiopathy (TMA)
Characterized by:• Capillary endothelial damage.• Microvascular formation of platelet/fibrin plugs.• This induces tissue ischemia• Damage to erythrocytes• Consumptive thrombocytopenia.
tHUS
• Occurs due to bacterial toxin production in colon.
• EHEC release verotoxin• Structurally similar to Shiga toxins released by
shigella (Stx1).• Stx1 and Stx2 (more severe)
EHEC
• Adheres to and efface intestinal cells and release Stx.
• Enters blood stream
• Transported by neutrophils.
• Stx binds to Gb3 (a glycolipid cell surface receptors) presented on endothelial cells of kidney and other target organs.
• Stx1 binds to and detaches easily from Gb3.• Stx2 binds and dissociates slowly from Gb3.
• At these sites, Stx disrupts protein systhesis, causing endothelial cell death and damage.
• Inflammatory and procoagulant cascade is induced and this promotes microvascular thrombosis.
aHUS (Sporadic)• Associated with invasive Streptococcus pneumoniae infection
(40% of cases).
• Renal endothelial cells, erythrocytes and platelets have Thomsen Friedenreich Ag (TAg) on their surface.
• TAg protected by neuraminic acid.
• Pneumococci has the enzyme neuramidase that cleaves neuraminic acid from the cell surface.
• TAg exposed.
• Anti-TAg IgM.
• Leads to antigen-antibody binding.
• Immune cascade activated.
• Leading to glomerular endothelial cell damage, hemolytic anemia, platelet aggregation and consumption and fall in GFR.
Other triggers
May occur in association with:• HIV, SLE, APS, malignancies, radiation, drugs.• Post transplant.• Influenza, CMV, EBV, Streptococci and
salmonella.
Complement dysregulation (Familial aHUS)
Complement gene mutations:• Factor H (FH gene).• Membrane Co-factor Protein (MCP gene)• Factor I Gene (FI gene)
• Autosomal dominant HUS-adults• Autosomal recessive HUS-childhood.• Both associated with poor prognosis.
• These genes code for proteins that inhibit activity of complement C3b.
• Deficiency causes unregulated amplification of the alternative pathway.
• Resulting in activated complement deposition on the surface of invading bacteria or damaged self tissue, such as apoptosed or inflamed renal endothelial cells.
FH, MCP, FI gene INHIBITS this pathway:
ADAMTS-13
• ADAMTS-13 (A Disintegrin like And Metalloprotease with ThromboSpondin type 1 repeats, number 13.)
• An enzyme produced by stellate cells in the liver.
• Located on chromosome 9q34.
• Acts as a von Willebrand factor cleaving protease.
• Degrades large multimeric forms of VWF by cleaving peptide bonds. (In other words, this enzyme cleaves VWF into smaller units)
• Deficiency of this enzyme, causes formation of ULVWF (Ultra Large) released into plasma.
• Circulating platelets preferentially binds to ULVWF strings (rather than to smaller VWF).
• Platelet aggregation continues leading to thrombotic microangiopathy (Hallmark).
• Embolisation of ULVWF platelet strings causes tissue ischaemia.
ADAMTS-13 deficiency
Familial:• usually in children.• rare.
Acquired:• more common in adults and older children.• Associated with presence of anti-ADAMTS13
antibodies. • Manifestation classically of frank TTP.
Management of Stx-HUS
• Symptomatic therapy• Specific therapy• Prevention• Prognosis
Symptomatic therapy
• Anemia• Thrombocytopenia• Fluid and electrolyte disturbances• Acute renal failure• Hypertension• Neurologic dysfunction• Other organ involvement.
Dialysis• No evidence that early dialysis effects clinical
outcome.
Indications for dialysis:• Signs and symptoms of uremia• Azotemia BUN 29-36mmol/L.• Severe fluid overload• Severe electrolyte abnormalities• Need for nutritional support in a child with oliguria or
anuria.
Specific therapy
• Plasma infusion and plasma exchange• Anti-thrombotic agents-not recommended.• Oral shiga toxin binding agent- not
recommended.• Tissue plasminogen activator.
Plasma exchange• Successful in many adults with TTP.
• No RCT that evaluate efficacy of PEx in children with StxHUS.
• ?shorten duration of acute renal failure.
• Meta analysis-no clinical benefit.
• Can be used in children with StxHUS and severe CNS involvement.
The role of plasma exchange in the treatment of severe forms of hemolytic-uremic syndrome in childhood.
AUSlavicek J; Puretic Z; Novak M; Sarnavka V; Benjak V; Glavas-Boras S; Thune S SOArtif Organs 1995 Jun;19(6):506-10.
• Analysis in 9 children from 1983-1993.
• 3 had GI Sxs, 5 had respiratory prodromes, 1 child developed HUS during the course of varicella.
• Five children were treated with PEx.
• Rapid recovery of renal function was observed in 5 patients whereas in 2 oliguric children the recovery of renal function ensued within 1 and 2 months, respectively.
• We suggest that PEx plays an important role in the early treatment of severe forms of HUS in children.
Escherichia coli O157:H7 and the Hemolytic–Uremic Syndrome
Thomas G. Boyce, M.D., David L. Swerdlow, M.D., and Patricia M. Griffin, M.DNEJM Volume 333:364-368 August 10, 1995
• No specific therapy has been proved effective in patients with E. coli O157:H7 infection.
• No proven efficacy of plasmapheresis, FFP and IVIG.
Prevention• Once patient infected with EHEC, attempts to prevent
progression from bloody diarrheal phase to postdiarrheal phase of HUS have been unsuccessful.
• Antibiotics and anti-motility drugs not recommended.
• Vigorous fluid repletion during diarrheal phase of illness is associated with less severe renal involvement.
Prognosis
• Hematologic manifestation resolve usually within one to two weeks.
• Mortality rate <5%.• Causes of death include hyperkalemia, CHF,
pulmonary hemorrhage.
Markers of poor prognosis
• WCC>20 on presentation
• Persistent oliguria/anuria.
• Renal histology showing a glomerular microangiopathy affecting >50% of glomeruli, arterial microangiopathy +/- cortical necrosis.
In summary
• HUS is a clinical syndrome characterized by MAHA, ARF and Thrombocytopenia.
• Thrombotic Microangiopathy (TMA) is the hallmark of disease pathogenesis.
• Stx or Non-Stx associated HUS.
• E.coli O157:H7 most common cause for Stx HUS.
• Strep pneumoniae for non-STx HUS.
• Familial form of HUS usually associated with complement dysregulation.
• Treatment of StxHUS mainly supportive with a good prognosis.