haemolytic uremic syndrome

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Haemolytic Uremic Syndrome (HUS)

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Page 1: Haemolytic Uremic Syndrome

Haemolytic Uremic Syndrome (HUS)

Page 2: Haemolytic Uremic Syndrome

Background

• A clinical syndrome

Characterized by:• Renal failure• Miroangiopathic hemolytic anemia• Thrombocytopenia

Page 3: Haemolytic Uremic Syndrome

• Most common cause of acute renal failure in children and is increasingly recognized in adults.

• First described by Gasser et al in 1955.

Page 4: Haemolytic Uremic Syndrome

Two main categories of HUS

• Shiga-like toxin associated HUS (Stx-HUS)

• Non-shiga-like toxin associated HUS(non-Stx-HUS)

Page 5: Haemolytic Uremic Syndrome

• Stx-HUS: (tHUS)D+ HUSD- HUS

• Non-StxHUS: (aHUS)SporadicFamilial

Page 6: Haemolytic Uremic Syndrome

Stx-associated HUS

In developed countries: • Escherichia coli serotype O157:H7 (EHEC)

most common.

In developing countries:• Shigella dysenteriae serotype 1.

Page 7: Haemolytic Uremic Syndrome
Page 8: Haemolytic Uremic Syndrome

Source of infection

• Human feco-oral transmission.• Milk and animal products (incompletely

cooked)• Veges, salads,drinking water contaminated by

bacteria shed in animal wastes.

Page 9: Haemolytic Uremic Syndrome

Pathogenesis

• Damage to endothelial cells is the primary event.

• Cardinal lesion composed of arterial and capillary microthrombi (thrombotic microangiopathy) and red blood cell fragmentation.

Page 10: Haemolytic Uremic Syndrome

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.

Page 11: Haemolytic Uremic Syndrome

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)

Page 12: Haemolytic Uremic Syndrome

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.

Page 13: Haemolytic Uremic Syndrome

• 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.

Page 14: Haemolytic Uremic Syndrome

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.

Page 15: Haemolytic Uremic Syndrome

• Leads to antigen-antibody binding.

• Immune cascade activated.

• Leading to glomerular endothelial cell damage, hemolytic anemia, platelet aggregation and consumption and fall in GFR.

Page 16: Haemolytic Uremic Syndrome

Other triggers

May occur in association with:• HIV, SLE, APS, malignancies, radiation, drugs.• Post transplant.• Influenza, CMV, EBV, Streptococci and

salmonella.

Page 17: Haemolytic Uremic Syndrome

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.

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• 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.

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FH, MCP, FI gene INHIBITS this pathway:

Page 20: Haemolytic Uremic Syndrome

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.

Page 21: Haemolytic Uremic Syndrome

• 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.

Page 22: Haemolytic Uremic Syndrome

• 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.

Page 23: Haemolytic Uremic Syndrome

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.

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Management of Stx-HUS

• Symptomatic therapy• Specific therapy• Prevention• Prognosis

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Symptomatic therapy

• Anemia• Thrombocytopenia• Fluid and electrolyte disturbances• Acute renal failure• Hypertension• Neurologic dysfunction• Other organ involvement.

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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.

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Specific therapy

• Plasma infusion and plasma exchange• Anti-thrombotic agents-not recommended.• Oral shiga toxin binding agent- not

recommended.• Tissue plasminogen activator.

Page 28: Haemolytic Uremic Syndrome

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.

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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.

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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.

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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.

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Prognosis

• Hematologic manifestation resolve usually within one to two weeks.

• Mortality rate <5%.• Causes of death include hyperkalemia, CHF,

pulmonary hemorrhage.

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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.

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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.