Thrombotic microangiopathy (TMA) refers to intraluminal platelet thrombosis in small blood vessels. TMA can be caused by conditions such as HUS, TTP, HIV, and malignant hypertension. In hemolytic uremic syndrome (HUS), TMA is caused by Shiga toxin from E. coli or other bacteria, which activates the alternative complement pathway and causes endothelial damage. The diagnostic approach to HUS and TMA involves excluding drugs, autoimmune hemolytic anemia, and other systemic diseases as causes before determining if the presentation matches Shiga toxin-HUS, atypical HUS, or TTP. Treatment of Shiga toxin-associated HUS is generally supportive with intravenous

1. Hemolytic Uremic Syndrome
Induced AKIh
From Pathogenesis to Bedside
Mohammed Abdel Gawad
Nephrologist
Kidney & Urology Center (KUC)
Alexandria – EGY
drgawad@gmail.com

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3.  What is meant by Thrombotic Microangiopathy
(TMA)?
 What are the causes of TMA?
 What is the mechanism of TMA in HUS?
 What is the diagnostic approach of HUS & TMA?
 What are the treatment protocols of HUS?
19
Talk Outline

4.  What is meant by Thrombotic Microangiopathy
(TMA)?
 What are the causes of TMA?
 What is the mechanism of TMA in HUS?
 What is the diagnostic approach of HUS & TMA?
 What are the treatment protocols of HUS?
19
Talk Outline

5. What is meant by Thrombotic
Microangiopathy (TMA)?
Intraluminal platelet thrombosis
Thrombocytopenia
Microangiopathic hemolytic
anemia
Consumption of
platelets
Hemolysis, Anemia, ↑LDH &
Bilirubin
119

6.  What is meant by Thrombotic Microangiopathy
(TMA)?
 What are the causes of TMA?
 What is the mechanism of TMA in HUS?
 What is the diagnostic approach of HUS & TMA?
 What are the treatment protocols of HUS?
Talk Outline
19

7. What are the causes of
TMA?
,HIV
TTP/HUS
18

8.  What is meant by Thrombotic Microangiopathy
(TMA)?
 What are the causes of TMA?
 What is the mechanism of TMA in HUS?
 What is the diagnostic approach of HUS & TMA?
 What are the treatment protocols of HUS?
QuestionsTalk Outline
18

9. What is the mechanism of
TMA in HUS?
Intraluminal platelet thrombosis
Thrombocytopenia
Microangiopathic hemolytic
anemia
Consumption of
platelets
Hemolysis, Anemia, ↑LDH &
Bilirubin
18

10. Intraluminal platelet thrombosis
Thrombocytopenia
Consumption of
platelets Shiga toxin HUS
Atypical HUS
Neuraminidase HUS
What is the mechanism of
TMA in TTP-HUS?
What is the mechanism of
TMA in HUS?
18

11. Intraluminal platelet thrombosis
Thrombocytopenia
Consumption of
platelets Shiga toxin HUS
Atypical HUS
Neuraminidase HUS
What is the mechanism of
TMA in TTP-HUS?
What is the mechanism of
TMA in HUS?
18

12. E. coli (STEC)
S. dysenteriae
`
watery or most
often bloody
diarrhea
`
Mead PS, Griffin PM. Lancet.1998;352:1207-1212.
Ruggenenti P, Remuzzi G.Lancet. 2011;378:1057-1058.
Shiga Toxin
Associated HUS
E.Coli:
Mostly the serotype O157:H7,
but also other serotypes, such
as O111:H8, O103:H2, O123,
O26, O145, and the O104:H4
strain of the recent German
outbreak
18

13. E. coli (STEC)
S. dysenteriae
watery or most
often bloody
diarrhea
Mead PS, Griffin PM. Lancet.1998;352:1207-1212.
Ruggenenti P, Remuzzi G.Lancet. 2011;378:1057-1058.
Shiga Toxin
Associated HUS
Shiga Toxin
Associated HUS
17

14. Shiga Toxin
Associated HUS
E. coli (STEC)
S. dysenteriae
watery or most
often bloody
diarrhea
Complement
activation by
alternative
pathway:
High plasma
levels of
complement
activation
products
Bb and C5b-9
were
measured in
children with
STEC-HUS
Morigi M et al. Blood. 2001;98:1828-1835.
Morigi M et al. J Immunol. 2011;187:172-180.
Shiga Toxin
Associated HUS
16

15. Intraluminal platelet thrombosis
Thrombocytopenia
Consumption of
platelets Shiga toxin HUS
Atypical HUS
What is the mechanism of
TMA in TTP-HUS?
What is the mechanism of
TMA in HUS?
Neuraminidase HUS
Toxin binds
endothelium
16

16. Neuraminidase
Associated HUS
In infants and children. Complicate pneumonia, or less
frequently, meningitis caused by S. pneumoniae
erythrocytes, platelets,
glomerular cells
Polyagglutination
Brandt J, Wong C, Mihm S, et al. Pediatrics. 2002;110:371-376.
8
Thomsen-Friedenreich antigen
Coomb’s +ve

17. Intraluminal platelet thrombosis
Thrombocytopenia
Consumption of
platelets Shiga toxin HUS
Atypical HUS
What is the mechanism of
TMA in TTP-HUS?
What is the mechanism of
TMA in HUS?
Neuraminidase HUS
Toxin binds
endothelium
N’ase
15

18. Atypical HUS
Caprioli J et al. Blood. 2006;108:1267-1279.
Manuelian T, et al. J Clin Invest. 2003;111:1181-1190.
Atypical HUS
Genetic mutation
14

19. Atypical HUSAtypical HUS
14Marina Noris. N Engl J Med 2009;361:1676-87

20. Atypical HUS
Caprioli J et al. Blood. 2006;108:1267-1279.
Manuelian T, et al. J Clin Invest. 2003;111:1181-1190.
Noris M, N Engl J Med. 2009;361:1676-1687.
Atypical HUS
Genetic mutation Precipitants of aHUS:
•Non-enteric bacterial and viral
Infections
•Immunotherapeutic agents (e.g.,
cyclosporine, tacrolimus)
•Malignant hypertension
•Transplantation
•Pregnancy
About 50% of patients with
sporadic aHUS show no
clear trigger (idiopathic HUS)
13

21. Atypical HUS
Caprioli J et al. Blood. 2006;108:1267-1279.
Manuelian T, et al. J Clin Invest. 2003;111:1181-1190.
Dragon-Durey et al. J Am Soc Nephrol. 2005;16:555-563.
Atypical HUS
Genetic mutation
Acquired defects
of CFH function
(inhibitory
antibodies),
reported in 5% to
10% of aHUS
13

22. Atypical HUSAtypical HUS
12

23. Intraluminal platelet thrombosis
Thrombocytopenia
Consumption of
platelets Shiga toxin HUS
Atypical HUS
What is the mechanism of
TMA in TTP-HUS?
What is the mechanism of
TMA in HUS?
Neuraminidase HUS
Toxin binds
endothelium
N’ase
Alternative
Complement
12

24. Intraluminal platelet thrombosis
Thrombocytopenia
Microangiopathic hemolytic
anemia
Consumption of
platelets
Hemolysis, Anemia, ↑LDH &
Bilirubin
What is the mechanism of TMA
in HUS?
Microangiopathic hemolytic
anemia
Hemolysis, Anemia, ↑LDH &
Bilirubin
12

25. HUS – MAHA
11

26. Pathogenesis – Pathology
Relationship
11
David Kavanagh. F1000Prime Reports 2014, 6:119

27.  What is meant by Thrombotic Microangiopathy
(TMA)?
 What are the causes of TMA?
 What is the mechanism of TMA in HUS?
 What is the diagnostic approach of HUS & TMA?
 What are the treatment protocols of HUS?
QuestionsTalk Outline
11

28. Marie Scully et al. British Journal
of Haematology, 2012, 158, 323–
335.
,HIV
DD of
thrombocytopenia
& MAHA
Systematic Approach of
Diagnosis
11

29. Marie Scully et al. British Journal
of Haematology, 2012, 158, 323–
335.
Systematic Approach
of Diagnosis
Step 1 –
Exclude Drugs
Systematic Approach of
Diagnosis
10

30. Piero Ruggenenti, Comprehensive
Clinical Nephrology. 4th
edition,
chapter 28, p353
Systematic Approach
of Diagnosis
Step 1 –
Exclude Drugs
Systematic Approach of
Diagnosis
10

31. - Marie Scully et al. British Journal of Haematology, 2012, 158, 323–335.
- Patton JF et al. Am J Hematol. 1994;47:94-99.
Systematic Approach
of Diagnosis
Step 2 – Autoimmune
Hemolysis
Step
3
10
Systematic Approach of
Diagnosis

32. - Marie Scully et al. British Journal of Haematology, 2012, 158, 323–335.
- Patton JF et al. Am J Hematol. 1994;47:94-99.
Systematic Approach
of Diagnosis
Step 2 – Autoimmune
Hemolysis
Step
3
10
Systematic Approach of
Diagnosis

33. Systematic Approach
of Diagnosis
Step 3 –
Coagulation Profile
Step 4 – Exclude other causes
9
Systematic Approach of
Diagnosis

34. Systematic Approach
of Diagnosis
Step 4 – Exclude other causes
8
Systematic Approach of
Diagnosis
DD Suggestive Criteria
Malignant
Hypertension
• Systolic BP >200 mmHg, diastolic BP >130 mmHg.
• MAHA and thrombocytopenia resolves with BP management.
Pre-
eclampsia
• New BP elevation and proteinuria after 20 weeks of
gestation in a pregnant woman.
Sepsis
• Hypotension
• More pronounced fever
• Raised white count with left shift.
• Blood cultures might be positive.
Pregnancy • Must be excluded.
Autoimmune
Disease
• ANA, RF, antiDNA, ACLA, lupus anticoagulant

35. Systematic Approach
of Diagnosis
Step 4 – Exclude other causes
,HIV
7
Systematic Approach of
Diagnosis

36. Systematic Approach
of Diagnosis
Step 4 – Exclude other causes
7
Systematic Approach of
Diagnosis

37. Systematic Approach
of Diagnosis
Step 4 – Exclude other causes
• TMA has been reported in
association with acute pancreatitis.
• Sometimes a number of days
after resolution of pancreatitis.
• All patients were successfully
treated with PEX and
corticosteroids (McDonald et al,
2009).
An association between
thrombocytopenia and
thyrotoxicosis has been
reported
7
Systematic Approach of
Diagnosis

38. Systematic Approach
of Diagnosis
Step 5 –
TTP vs HUS
Shiga toxin-
HUS
Neuraminidase
-HUS
Atypical HUS TTP
7
Systematic Approach of
Diagnosis

39. Systematic Approach
of Diagnosis
Shiga toxin-
HUS
Neuraminidase
-HUS
- Less than 2 years old
- Respiratory distress,
neurologic
involvement,
and coma.
Mead PS, Griffin PM. Lancet. 1998;352:1207-1212.
Step 5 – TTP vs HUS
6
Systematic Approach of
Diagnosis
- Occurs primarily in children, (except
in epidemics with any age)
-Watery or bloody diarrhoea.
- Stool Culture: detection of E. coli
O157:H7 and other STEC and their
products in stool cultures (sorbitol-
containing MacConkey agar - SMAC)

40. Systematic Approach
of Diagnosis
Shiga toxin-
HUS
Neuraminidase
-HUS
- Less than 2 years old
- Respiratory distress,
neurologic
involvement,
and coma.
Mead PS, Griffin PM. Lancet. 1998;352:1207-1212.
Step 5 – TTP vs HUS
6
Systematic Approach of
Diagnosis
- Occurs primarily in children, (except
in epidemics with any age)
-Watery or bloody diarrhoea.
- Stool Culture: detection of E. coli
O157:H7 and other STEC and their
products in stool cultures (sorbitol-
containing MacConkey agar - SMAC)

41. Systematic Approach
of Diagnosis
Neuraminidase
-HUS
- Less than 2 years old
- Respiratory distress,
neurologic
involvement,
and coma.
Mead PS, Griffin PM. Lancet. 1998;352:1207-1212.
Step 5 – TTP vs HUS
6
Systematic Approach of
Diagnosis

42. Systematic Approach
of Diagnosis
Step 5 –
TTP vs HUS
Shiga toxin-
HUS
Neuraminidase
-HUS
Atypical HUS TTP
6
Systematic Approach of
Diagnosis

43. Systematic Approach
of Diagnosis
Atypical HUS TTP
Step 5 – TTP vs HUS
Difficult to distinguish on clinical grounds only
Moschcowitz E. Mt Sinai J Med. 2003;70:352-355.
5
Systematic Approach of
Diagnosis

44. Systematic Approach
of Diagnosis
Atypical HUS TTP
Step 5 – TTP vs HUS
Difficult to distinguish on clinical grounds only
Differential diagnosis of aHUS is made on exclusion:
• Of infections by STEC or neuraminidase - producing
S.pneumoniae,
• Of ADAMTS13 deficiency,
• Of Systemic-associated diseases
5
Systematic Approach of
Diagnosis

45. Systematic Approach
of Diagnosis
Atypical HUS TTP
Step 5 – TTP vs HUS
Difficult to distinguish on clinical grounds only
Moschcowitz E. Mt Sinai J Med. 2003;70:352-355.
Eknoyan G, Riggs SA. Am J Nephrol. 1986;6:117-131. 5
Systematic Approach of
Diagnosis

46. Systematic Approach
of Diagnosis
Step 1: Exclusion of drugs
Step 2: Exclusion of Autoimmune hemolysis
Step 3: Coagulation Profile
Step 4: Exclusion of other systemic causes
Step 5: TTP vs HUS?
5
Systematic Approach
of Diagnosis
Diagnosis
Message

47.  What is meant by Thrombotic Microangiopathy
(TMA)?
 What are the causes of TMA?
 What is the mechanism of TMA in HUS?
 What is the diagnostic approach of HUS & TMA?
 What are the treatment protocols of HUS?
Questions
4
Talk Outline

48. Shiga Toxin
Associated HUS
E. coli (STEC)
S. dysenteriae
watery or most
often bloody
diarrhea
Ruggenenti P, Remuzzi G.Lancet. 2011;378:1057-1058.
Morigi M et al. J Immunol. 2011;187:172-180.
4
Complement
activation by
alternative
pathway:
High plasma
levels of
complement
activation
products
Bb and C5b-9
were
measured in
children with
STEC-HUS

49. Shiga Toxin Associated HUS
Treatment
Generally Supportive (including RRT if required)
No role for Anticoagulation
No role for Antitimotility agents
4
IV isotonic volume expansion
(as soon as an E. coli O157:H7 infection is suspected),
limit the severity of AKI and the need for RRT
Ake JA et al. Pediatrics. 2005;115:e673-e680

50. Generally Supportive (including RRT if required)
No role for Antibiotics except:
1.Patients presenting with bacteremia
2.HUS, hemorrhagic colitis and HUS caused by Shigella
dysentery type 1
3.Azithromycin had some benefit on the duration of bacterial
shedding in adult patients from the German O104:H4
epidemic
Shiga Toxin Associated HUS
Treatment
3
Nitschke M et al. JAMA. 2012;307:1046-1052.
Van Dyck M, et al. Pediatr Nephrol. 2004;19:688-690.

51. Generally Supportive (including RRT if required)
Is there a role for plasma exchange?
No prospective RCTs are available
ADULT patients with severe AKI and CNS involvement
plasma therapy may decrease overall mortality of STEC
O157:H7–associated HUS.
Dundas S et al. Lancet. 1999;354:1327-1330.
Carter AO et al. N Engl J Med. 1987;317:1496-1500.
Shiga Toxin Associated HUS
Treatment
3

52. Atypical HUS
Caprioli J et al. Blood. 2006;108:1267-1279.
Manuelian T, et al. J Clin Invest. 2003;111:1181-1190.
2
Genetic mutation
Acquired defects
of CFH function
(inhibitory
antibodies),
reported in 5% to
10% of aHUS

53. Atypical HUS Treatment
2
When to start? within 24 hours of diagnosis
Frequency: daily initially, then determined by clinical
response
Plasma exchange (1 to 2 plasma volumes/day)
vs Plasma infusion (20 to 30 ml/kg/day)

54. Atypical HUS Treatment
Plasma exchange (1 to 2 plasma volumes/day)
vs Plasma infusion (20 to 30 ml/kg/day)
Plasma Exchange is superior to Infusion:
1.Supply larger amounts of plasma while avoiding fluid
overload.
2.Removal of mutant CFH.
3.Remove anti-CFH antibodies, but the effect is usually
transient.
Noris M, Remuzzi G. N Engl J Med. 2009;361:1676-1687.
Dragon-Durey MA, et al. J Am Soc Nephrol. 2005;16:555-563.
2

55. Atypical HUSAtypical HUS
Marina Noris. N Engl J Med 2009;361:1676-87
M. Kathryn Liszewski. The Rheumatologist, February 2010 1

56. Atypical HUSAtypical HUS
Marina Noris. N Engl J Med 2009;361:1676-87
M. Kathryn Liszewski. The Rheumatologist, February 2010
MCP is expressed on the surface of all cells (except RBC)
1

57. Atypical HUS Treatment
Immunosuppressants (corticosteroids
and azathioprine or mycophenolate mofetil)
combined with plasma exchange allowed long-
term dialysis-free survival in 60% to 70% of
patients.
Dragon-Durey MA et al. J Am Soc Nephrol. 2010;21:2180-2187.
Plasma exchange
1

58. Atypical HUS Treatment
Licht C et al. J Am Soc Nephrol. 2011;22:197A.
Greenbaum LA et al. J Am Soc Nephrol. 2011;22:197A.
1
Atypical HUS Treatment
Duration of therapy??
Cost??

59. Atypical HUSAtypical HUS
0
Living related donation is contraindicated given the high risk of
recurrence
Living related donation may be risky to donors because
uninephrectomy may precipitate aHUS in complement gene
mutation carriers.

60. Atypical HUSAtypical HUS
0

61. HUS Treatment
0
STEC - HUS Atypical HUS
• General supportive
• IV isotonic hydration
• No anticoagulation
• No antimotility drugs
• No antibiotics (except some
situations)
• ??? PEX
• Plasma Therapy (PEX is
better) +
Immunosuppressives
• Eculizmab
• Renal ± Liver
Transplantation
Treatment
Message

62. First Reported HUS Cases
Gasser C, Gautier E, Steck A, et al. Schweiz Med Wochenschr. 1955;85:905-
909.
0

63. Gawad
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