1. HaemolyticUremic Syndrome (HUS)

2. Background A clinical syndrome Characterized by: Renal failure Miroangiopathic hemolytic anemia Thrombocytopenia

3. Most common cause of acute renal failure in children and is increasingly recognized in adults. First described by Gasser et al in 1955.

4. Two main categories of HUS Shiga-like toxin associated HUS (Stx-HUS) Non-shiga-like toxin associated HUS (non-Stx-HUS)

5. Stx-HUS: (tHUS) D+ HUS D- HUS Non-StxHUS: (aHUS) Sporadic Familial

6. Stx-associated HUS In developed countries: Escherichia coli serotype O157:H7 (EHEC) most common. In developing countries: Shigella dysenteriae serotype 1.

8. Source of infection Human feco-oral transmission. Milk and animal products (incompletely cooked) Veges, salads,drinking water contaminated by bacteria shed in animal wastes.

9. Pathogenesis Damage to endothelial cells is the primary event. Cardinal lesion composed of arterial and capillary microthrombi (thrombotic microangiopathy) and red blood cell fragmentation.

10. 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.

11. 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)

12. 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.

13. 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.

14. 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.

15. Leads to antigen-antibody binding. Immune cascade activated. Leading to glomerular endothelial cell damage, hemolytic anemia, platelet aggregation and consumption and fall in GFR.

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

17. 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.

18. 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.

19. FH, MCP, FI gene INHIBITS this pathway:

20. ADAMTS-13 ADAMTS-13 (ADisintegrin like And Metalloprotease with ThromboSpondin type 1 repeats, number 13.) An enzyme produced by stellate cells in the liver. Located on chromosome 9q34.

21. 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.

22. 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.

23. 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.

24. Management of Stx-HUS Symptomatic therapy Specific therapy Prevention Prognosis

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

26. 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.

27. Specific therapy Plasma infusion and plasma exchange Anti-thrombotic agents-not recommended. Oral shiga toxin binding agent- not recommended. Tissue plasminogen activator.

28. 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.

29. 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.

30. Escherichia coli O157:H7 and the Hemolytic–Uremic SyndromeThomas G. Boyce, M.D., David L. Swerdlow, M.D., and Patricia M. Griffin, M.DNEJM Volume 333:364-368August 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.

31. 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.

32. Prognosis Hematologic manifestation resolve usually within one to two weeks. Mortality rate <5%. Causes of death include hyperkalemia, CHF, pulmonary hemorrhage.

33. 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.

34. 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.