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Hemolytic Uremic Syndrome

Hemolytic Uremic Syndrome. Beatrice Goilav, M.D. Pediatric Nephrology Children’s Hospital at Montefiore Albert Einstein College of Medicine. Disclosures. Nothing to disclose. Outline. Background/Epidemiology and other things to know on “classical” diarrhea-associated HUS

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Hemolytic Uremic Syndrome

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  1. Hemolytic Uremic Syndrome Beatrice Goilav, M.D. Pediatric Nephrology Children’s Hospital at Montefiore Albert Einstein College of Medicine

  2. Disclosures Nothing to disclose.

  3. Outline • Background/Epidemiology and other things to know on “classical” diarrhea-associated HUS • The “funky” types of HUS • Atypical, non-diarrhea associated, recurrent, familial • What you should know about atypical HUS and what to do with that information

  4. THE HISTORY OF HUS

  5. Gasser C, et al. 1955 • First description • Self-limited illness associated with a prodrome of diarrhea that results in spontaneous recovery Einstein’s first job was here I was born here Conrad Gasser (1912-1982)

  6. DIAGNOSTIC COMPONENTS ANDHISTOPATHOLOGY

  7. Hemolytic Uremic Syndrome (HUS) • Triad • Microangiopathic hemolytic anemia • Thrombocytopenia • Acute kidney injury • Thrombotic Microangiopathy (TMA) • Hemolytic Uremic Syndrome • Thrombotic Thrombocytopenic Purpura

  8. HemolyticAnemia • Microangiopathic hemolytic anemia with erythrocyte fragmentation • Coombs negative • Plasma LDH elevated • Haptoglobin decreased • Most sensitive marker to track resolution of intravascular hemolysis • Severity does not correlate with clinical outcome • Red cell production increased

  9. Thrombocytopenia • Variable and transient • May be missed • Consumption of platelets • Majority of platelets removed in reticuloendothelial system • Significant bleeding rare! • Slightly pro-thrombotic state

  10. Acute Kidney Injury • Abrupt • Oligoanuria • Proteinuria • Hypertension • Severe and difficult to control in atypical forms • Absent or mild in infection-associated form – delayed to recovery period

  11. Thrombotic Microangiopathy (TMA) • Histopathological term • Characterized by presence of • Platelet-fibrin thrombi within the vascular lumen • Injury to endothelial cells with separation from underlying basement membrane • Deposition of eosinophilic material

  12. Risk Factors for Development of HUS • Female gender • Severe colitis • Fever • Leukocytosis • Also: • Younger age • Antimotility agents • Antibiotics • Alterations in gene for factor H • Implicated in pathophysiology of atypical HUS

  13. Some Statistical Data • Most common cause of acute kidney injury in childhood • Incidence: 3-5/100,000 population in children age 1-18 • Gradual decline from early childhood to adolescence • Significant morbidity and mortality in acute phase • Mortality: 3-5%, usually associated with severe extra-renal disease • Primary diagnosis for up to 4.5% of children on chronic renal replacement therapy

  14. M & M • Mortality • 3-5% • Serious extra-renal complications • 20% • Need for acute dialysis • 40% • Persistent renal injury • 20%; hypertension, proteinuria, reduced GFR

  15. Terminology/Categories

  16. D+ HUS

  17. Diagnosis • Clinical - Abrupt onset of illness • Recognized within 24 hours of onset • Lethargy • Pallor • Oliguria • Laboratory abnormalities: • Coombs-negative anemia and thrombocytopenia • Rising BUN/Creatinine • Elevated LDH • Low haptoglobin

  18. Clinical Time Course • Ingestion of bacteria • Enterocolitis within 2-3 days • Bloody stools in >85% • Fever • Severe abdominal pain • Most cases: self-limited, complete resolution • 5-10% progress to HUS • Monophasic illness

  19. Route of Infection

  20. Most Common Etiology Worldwide • Enterohemorrhagic E. coli (EHEC) O157:H7 • D+ HUS (typical) • Produces Shiga toxin (Stx) 1 and/or 2 • Encoded on a phage • Other E. coli strains also produce Stx • Called Stx-producing E. coli (STEC) • Over 400 seropathotypes

  21. Pathogenesis • Shiga toxin (Stx)-induced injury to endothelial cells • Activation of prothrombotic coagulation cascade • Release of inflammatory mediators and chemokines

  22. Molecular Risk Assessment • Association of virulence genes with severity of disease • Presence or absence of genes (binary typing) produces genetic fingerprint for each isolate • Identify strains that have greater potential to cause harm = molecular risk assessment

  23. Binary Typing of Virulence Genes • Distribution of 41 virulence genes in STEC isolates • “Virulence bar code” for each isolate • Integrated epidemiological data • Allows some prediction of clinical course Brandt SM et al. Appl Environ Microbiol. 2011 Apr;77(7):2458-70.

  24. Brandt SM et al. Appl Environ Microbiol. 2011 Apr;77(7):2458-70.

  25. Virulence Factors • Seropathotype (SPT) classification identifies STEC serotypes linked to outbreaks and/or serious disease • SPT A (O157:H7, O157:NM) and SPT B (O26:H11/NM, O103:H2, O111:H8/NM, O121:H19, O145:NM) associated with outbreaks and HUS • SPT C (e.g., O5:NM, O91:H21, O113:H21, O121:NM, O128:H2) associated with sporadic cases of HUS but not with outbreaks • SPT Dincludes remainder of STEC serotypes that have been reported to cause sporadic disease and association with diarrhea but not HUS • SPT Enot associated with human illness

  26. Therapy • Nothing proven • Intensive, supportive medical care • Dialysis if: • Anuria x 24 h • Oliguria (urine output <0.5ml/kg/h) x 48-72 h • pRBC Transfusion if: • Hemoglobin <6 g/dl • Ineffective treatments are: • Antiplatelet drugs, fibrinolytic agents, IVIG, high-dose steroids, plasmapheresis, and oral Stx-binding agents

  27. Careful Monitoring • Electrolyte abnormalities • Hyponatremia • Hypocalcemia • LDH, serum creatinine, Hgb, platelets • Watch out for : • Seizures • Pancreatitis • Myocardial dysfunction • Adult respiratory distress syndrome • Sudden neurologic deterioration

  28. Prevention of HUS – The Scientific Approach • Subcutaneous mouse vaccine against stx and intestinal zonula occludens toxins • Decreased shedding of E. coli O157:H7 • Good news: mice TOLERATED vaccine WELL • Bad news: MICE tolerated vaccine well

  29. Prevention of HUS – The Useful Approach • Changes in feed provided to cattle • Tighter regulation of meat processing plants • Irradiation of food and beverages • No antibiotics in children with bloody diarrhea • Prompt hospitalization and administration of isotonic parenteral fluids • Prevent vascular injury in glomerular microcirculation • Isolate sick individual from other family members

  30. D- HUS

  31. Atypical, Sporadic, Non-Familial HUS • Pneumococcus-related disease • Younger children • Number of cases requiring dialysis is higher • Worse prognosis compared with STEC-related HUS • Other causes: • HIV infection, use of calcineurin inhibitors, OCP, SLE (usually in presence of antiphospholipid syndrome), and HELLP syndrome

  32. Atypical HUS

  33. Atypical HUS • Annual incidence of genetic forms of aHUS: • 10% of D+HUS • 3-5 cases per 1 million • Strong association between aHUS and mutations and/or polymorphisms in complement gene (regulatory and activation proteins) • 50% of cases linked to genetic mutations in alternate cascade

  34. Modulators of Alternate Complement Cascade • Loss-of-function mutations in regulatory proteins or gain-of-function mutations in factor B and complement 3 • Three most common defects: • Mutation in factor H: 25-35% not to be confused with • Mutation in factor I: 5-10% • Mutation in membrane co-factor protein (MCP = CD46): 3-5% • Deficiency in factor H-related proteins (CFHR1-5) • Polymorphic delCFHR1/3 deletion strongly associated with CFH auto-antibodies • aHUS due to CFH auto-antibodies more common in children

  35. Clinical Course of aHUS • Onset of syndrome frequently preceded by environmental insult (e.g., infection) • Typically infants/young children • C3 level may be normal • CFH mutations predominantly result in impaired ability of CFH to interact with cell surfaces, but ability to regulate plasma C3 preserved

  36. Clinical Relevance of Genetic Testing • Important to test for CFH auto-antibodies - strategies to reduce auto-antibody titer (e.g. plasma exchange) • Higher relapse rate • Increased likelihood of progression to end-stage kidney disease • High rate of recurrence after kidney transplant • Factor H or I mutation >> MCP mutation • MCP present in transplanted kidney – prevents complement-mediated injury to allograft

  37. Therapy of Genetic aHUS • Plasma • Intermittent infusions or via plasmapheresis • Treatment intensity guided by disease activity: • Platelet count • LDH level • Serum creatinine concentration • If suspecting genetic form of aHUS, initiate daily plasma therapy promptly • Combined kidney/liver transplant • For cases with factor H and factor I mutations • Hepatic production of normal complement regulators

  38. Plasma Therapy Not THIS one!

  39. Plasma Therapy

  40. Complement 5 Protein Critical role in development of aHUS CFH-deficient animals expressing mutant CFHD16–20 protein develop spontaneous aHUS C5 knockout in this model results in resistance to aHUS.

  41. Eculizumab • Recombinant, humanized, monoclonal Ab produced from mouse myeloma cells • Approved for treatment of paroxysmal nocturnal hemoglobinuria (PNH) • Reduces intravascular hemolysis, anemia, thrombotic events, and transfusion requirements in PNH • Targets complement protein C5 and prevents generation of proinflammatory peptide C5a and cytotoxic membrane attack complex C5b-9

  42. Regimen Weekly infusions with gradual increase in dosing with biweekly maintenance therapy Shown to completely block complement activity Complement blockade confirmed by CH50 measurements Dosing and pharmacokinetics in children are underway in international multi-center study – Children’s Hospital at Montefiore to be added as site within next 2 months

  43. Thrombotic Thrombocytopenic Purpura

  44. TTP – Moschcowitz Syndrome An acute febrile pleiochromic anemia with hyaline thrombosis of terminal arterioles and capillaries: An undescribed disease. Archives of Internal Medicine, Chicago, 1925, 36: 89.

  45. Deficiency of von Willebrand Protease (ADAMTS13) = a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 • Thrombocytopenia • Microangiopathic hemolytic anemia • Neurological symptoms • Renal dysfunction • Fever

  46. Role of ADAMTS13 (or a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13)

  47. ADAMTS13 (you know what is supposed to be written here)Deficiency • Cause: • Rare: loss-of-function mutation (Congenital TTP) • Acquired inhibitor: IgG auto-antibody • Associated with use of Clopidogrel and Ticlopidine • Effect: • Ultra-large vWF multimers

  48. ADAMTS13 (guess what?) Deficiency • Enzyme activity of <5% is primary cause of microvascular thrombosis • Enzyme activity <30% in several disease and physiological states • Thrombi found at arteriolar-capillary junction – area of high shear stress • Affected organs: • Brain, heart, spleen, kidney, pancreas, adrenals, lungs, and eyes

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