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 ( )

6. DIAGNOSTIC COMPONENTS AND HISTOPATHOLOGY

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

9. Hemolytic Anemia Severity does not correlate with clinical outcome
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

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

11. 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

12. 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

13. 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

14. 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

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

16. Terminology/Categories
Comment
D+ HUS
Patient presents with prodrome of diarrhea in past 2 weeks
Typical HUS
D+ HUS, diagnosis made in retrospect; single, self-limited event
Atypical HUS
Any pattern of clinical presentation other than D+ HUS – implies complement dysregulation
Recurrent or relapsing HUS
Repeat episode of same clinical features, implies repeat injury to kidneys – strongly suggests genetic or autoimmune risk factor
Thrombotic microangiopathy, glomerular thrombotic microangiopathy
Pathological descriptive terms
Familial HUS
Unclear term. Not distinguishing between
Synchronous HUS = several family members infected with EHEC at the same time;
and
Asynchronous HUS = implies inherited risk factor

17. D+ HUS

18. 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

19. Clinical Time Course Monophasic illness 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

20. Route of Infection

21. 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

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

23. 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

24. 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 Apr;77(7):

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

26. 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 D includes remainder of STEC serotypes that have been reported to cause sporadic disease and association with diarrhea but not HUS
SPT E not associated with human illness

27. Therapy Nothing proven Intensive, supportive medical care Dialysis if:
Anuria x 24 h
Oliguria (urine output <0.5ml/kg/h) x 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

28. 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

29. 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

30. 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

31. D- HUS

32. 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

33. Atypical HUS

34. 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

36. 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

37. 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

38. 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

39. 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

40. Plasma Therapy
Not THIS one!

41. Plasma Therapy

42. 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.

43. 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

44. 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

45. Thrombotic Thrombocytopenic Purpura

46. 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.

47. 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

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

49. 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

50. 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

51. Outcome of TTP Mortality: What made the difference? Historically: 95%
Today: 20%
What made the difference?
Plasma therapy

52. The Weird Ones HUS can be also caused by: Cobalamin deficiency
Defect in methylmalonic aciduria and homocystinuria gene (MMACHC)
Quinine/Quinidine
Found in tonic water and tablets that prevent muscle cramps
Autoantibodies to ?
Really rare ones:
Use of anti-VEGF monoclonal antibodies
Disseminated adenocarcinoma

53. Questions?
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