1. Advancements in the Understanding of atypical Haemolytic Uraemic Syndrome (aHUS)

2. Program Objectives
Highlight that atypical haemolytic uraemic Syndrome (aHUS) is a genetic, life-threatening, and chronic disease
Explain the role of complement in aHUS
Demonstrate how complement-amplifying conditions place patients with aHUS at high risk for TMA manifestations
How to approach a differential diagnoses of aHUS
Explore limitations of historical supportive care options

3. aHUS: Complement-Mediated Thrombotic Microangiopathy (TMA)1-4
Due to a genetic deficiency of complement regulators, aHUS is a permanent, ongoing disease of systemic, complement-mediated TMA1,2
Defined by the clinical characteristics of TMA:
Decreased platelet count1
Evidence of microangiopathic haemolysis3
Evidence of organ impairment/damage (e.g., serum creatinine >ULN)2,3
Complement-amplifying conditions may unmask aHUS4
Affects both adults and children2
References: 1. Noris M et al. N Engl J Med. 2009;361: Noris M et al. Clin J Am Soc Nephrol. 2010;5: Desch K et al. JASN. 2007;18: Kavanagh D et al. British Medical Bulletin. 2006; 77 and 78: 5-22.

4. Distinct Pathophysiologies Differentiate aHUS and TTP
Genetic, complement-mediated TMA (aHUS)
Underlying cause: chronic, uncontrolled complement activity1-5
Genetic defects in activators and/or inhibitors lead to chronic activity of the complement system,
causing endothelial cell damage and continuous
platelet aggregation1-5
Treatment goal: Address underlying
chronic complement activity
Severe ADAMTS13 deficiency (TTP)
Underlying cause: severe deficiency in ADAMTS13 activity (≤5%) 6-10
Insufficient ADAMTS13 activity (≤5%) leaves von
Willebrand factor uncleaved, causing excessive
platelet aggregation8,7,11,12
Treatment goal: Removal of
autoantibodies against ADAMTS13
Normal
ADAMTS13
activity
ADAMTS13
deficiency
vWF cleaved
vWF uncleaved
References: 1. Noris M, Caprioli J, Bresin E, et al. Clin J Am Soc Nephrol. 2010;5: Noris M, Remuzzi G. N Engl J Med. 2009;361: Holers VM. Immunol Rev. 2008;223: Loirat C, Frémeaux-Bacchi V. Orphanet J Rare Dis. 2011;6: Fang CJ, Richards A, Liszewski MK, et al. Br J Haematol. 2008;143: Hirt-Minkowski P, Dickenmann M, Schifferli JA. Nephron Clin Pract. 2010;114:c219-c Tsai H-M. Int J Hematol. 2010;91: Sadler JE. Blood. 2008; 112: Bianchi V, Robles R, Alberio L, et al. Blood. 2002;100: Barbot J, Costa E, Guerra M, et al. Br J Haematol. 2001;113: Moake JL. N Engl J Med. 2002;347: Tsai H-M. Am J Med. 2013;126:

5. aHUS: A Chronic, Complement-Mediated TMA with Life-Threatening Consequences1,2
Patients diagnosed with aHUS are at immediate and ongoing risk of progressive clinical deterioration despite intensive use of Plasma Exchange/Plasma Infusion (PE/PI)1,2
aHUS may result in death and progressive damage
79% of aHUS patients die, require dialysis or have permanent renal damage within 3 years1
33 to 40% of patients die or progress to end-stage renal disease with the first clinical manifestation despite PE/PI1,2
1.00
Up to 70% of patients
(with the most common
mutation, CFH) die,
require dialysis, or
have permanent renal damage within
1 year2
0.75
Cumulative Fraction of Patients Free of Events
0.50
0.25
94% of patients received PE/PI
for the first TMA manifestation2
0.00 3 6
12.5
Follow Up (months)
Modified from Caprioli J et al. Blood CFH mutation depicted.
References: 1. Noris M, Caprioli J, Bresin E, et al. Clin J Am Soc Nephrol. 2010;5: Caprioli J, Noris M, Brioschi S, et al; for the International Registry of Recurrent and Familial HUS/TTP. Blood. 2006;108:

6. PE/PI Does Not Reduce Morbidity in aHUS1
Despite PE/PI, the renal outcome for patients with aHUS has remained poor2
Renal outcome one year after aHUS diagnosis was comparable between patients with PE/PI and without PE/PI1
P=0.98
34%
33%
Received PE/PI*
No PE/PI
% of patients
Patients requiring dialysis at 1 year1
Study description: Analysis of patients from the aHUS registry of the GPN (working Group for Pediatric Nephrology). 141 patients were included in the registry at the time of this analysis. Data on treatment of initial manifestations was available for 99 patients.
Footnote: *Forty-two (38/89) percent of patients received PE. 48% (45/93) received PI, and 22 patients received both PE and PI.
References: 1. Riedl M, Hofer J, A Rosales, et al. Initial plasma therapy in patients with atypical HUS: No negative predictive value for the outcome after one year. Klin Padiatr. 2011;223-P Fakhouri F et al. Am J Kidney Dis. 2013;1:40-8.

7. No Identifiable Mutation Identifiable Mutation
Regardless of Whether or not a Mutation is Identified, Patients with aHUS have Similarly Devastating Outcomes1,2
Consequences
No Identifiable Mutation
Identifiable Mutation
% of patients that died or progressed to ESRD within the first clinical manifestation1,2
28-37%
40-44%
% of patients that died, required dialysis, or had permanent renal damage within the first year after diagnosis2
65%
63%
% of Death, ESRD, or permanent renal damage: Outcome at 3 years1
82%
76%
Footnotes: ESRD = end state renal disease.
References: 1. Noris M et al. Clin J Am Soc Nephrol. 2010;5: Caprioli et al. Blood. 2006;108:

8. The Role of Complement in aHUS

9. Natural Complement Regulators are Required for Control of the Complement System1-3
The complement system is part of the natural (innate) protective immune system1
Activity is continuously occurring by a spontaneous process called “tick-over” which enables rapid immune responses1
Natural inhibitors of complement keep amplification in check and prevent uncontrolled complement activity2
When unregulated, complement activity can lead to destructive consequences, including TMA lesions and progressive organ damage3
References: 1. Holers VM et al. Immunol Rev. 2008;223: Zipfel PF et al. Curr Opin Nephrol Hypertens. 2010;4: Legendre CM, Licht C, Muus P, et al. N Engl J Med. 2013;368:

10. Immune Complex Clearance Microbial Opsonisation
Natural Inhibitors are Required for Control of the Complement System1-17
Lectin Pathway
Classical Pathway
Alternative Pathway
iC3b
C3-Convertase
C3b
Immune Complex Clearance
Microbial Opsonisation
Weak Anaphylatoxin C3a
C3 + H2O: always active (chronic) C3
Amplification
Natural Inhibitors: Factor I, Factor H, MCP
Proximal
Thrombomodulin
C5b-9 (Membrane Attack Complex)
Cell lysis
Proinflammatory
Platelet activation
Leukocyte activation
Endothelial activation
Prothrombotic
C5a
Potent anaphylatoxin
Chemotaxis C5
C5-Convertase
Terminal
C5b C6 C7 C8 C9
References: 1. Zipfel PF et al. Vaccine 2008;26(Suppl 8):I67-I74. 2.Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4: Walport MJ. N Engl J Med. 2001;344: Rother RP et al. Nat Biotechnol. 2007;25: Meyers G et al. Blood. 2007;110:abs Hill A et al. Br J Haematol. 2010;149: Hillmen P et al. Am J Hematol. 2010;85: Parker C et al. Blood. 2005;106: Hillmen P et al. N Engl J Med. 1995;333: Nishimura J et al. Medicine. (Baltimore) 2004;83: Caprioli J et al. Blood. 2006;108: Noris M et al. Clin J Am Soc Nephrol. 2010;5: George JN. Blood. 2010;116: Loirat C et al. Pediatr Nephrol. 2008;23: Ståhl AL et al. Blood. 2008;111: Hosler GA et al. Arch Pathol Lab Med. 2003;127; Ariceta G et al. Pediatr Nephrol. 2009;24:

11. Immune Complex Clearance Microbial Opsonisation
In aHUS, Chronic Uncontrolled Complement Activity Leads to Devastating Consequences1-17
Lectin Pathway
Classical Pathway
Alternative Pathway
Immune Complex Clearance
Microbial Opsonisation C3
C3 + H2O: always active (chronic)
Amplification
Natural Inhibitors: Factor H, Factor I, MCP −
Proximal
Weak Anaphylatoxin C3a
C3b
Thrombomodulin −
iC3b
C3-Convertase
Gain of Function
Mutations:
C3, CFB +
C5-Convertase C5
Terminal
C5b C6 C7 C8 C9
C5a
Potent anaphylatoxin
Chemotaxis
Proinflammatory
Leukocyte activation
Endothelial activation
Prothrombotic
C5b-9 (Membrane Attack Complex)
Cell lysis
Proinflammatory
Platelet activation
Leukocyte activation
Endothelial activation
Prothrombotic
Consequences
Consequences
Anaphylaxis
Inflammation
Thrombosis
Haemolysis
Inflammation
Thrombosis
Tissue Damage
References: 1. Zipfel PF et al. Vaccine 2008;26(Suppl 8):I67-I74. 2.Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4: Walport MJ. N Engl J Med. 2001;344: Rother RP et al. Nat Biotechnol. 2007;25: Meyers G et al. Blood. 2007;110:abs Hill A et al. Br J Haematol. 2010;149: Hillmen P et al. Am J Hematol. 2010;85: Parker C et al. Blood. 2005;106: Hillmen P et al. N Engl J Med. 1995;333: Nishimura J et al. Medicine. (Baltimore) 2004;83: Caprioli J et al. Blood. 2006;108: Noris M et al. Clin J Am Soc Nephrol. 2010;5: George JN. Blood. 2010;116: Loirat C et al. Pediatr Nephrol. 2008;23: Ståhl AL et al. Blood. 2008;111: Hosler GA et al. Arch Pathol Lab Med. 2003;127; Ariceta G et al. Pediatr Nephrol. 2009;24:

12. Elevated Baseline Complement Activity Chronic Complement Activity
Chronic, Uncontrolled Complement Activity Results in Continuous Endothelial Damage and Ongoing Risk of TMA1
Elevated Baseline Complement Activity
Chronic Complement Activity
The assembly of multiple C5b-9 complexes on the surface of endothelial cells causes endothelial injury and platelet activation2-5
Binding of C5a to the C5a receptor, results in a decrease in the endothelium’s anti-complement and anti-thrombotic properties2,4,6,7
red blood cell
leukocyte
platelet
activated leukocyte
activated platelet
vWF
prothrombotic factors
schistocyte
Footnotes: vWF = Von Willebrand Factor; Image for illustrative purposes only, objects are not to scale. References: 1. Noris M and Remuzzi G Nat Rev Nephrol. 2014;10(3): Noris M, Mescia F, Remuzzi G. Nat Rev Nephrol. 2012;8: Barbour T, Johnson S, Cohney S, et al. Nephrol Dial Transplant. 2012;27: Fang CJ, Richards A, Liszewski MK, et al. Br J Haematol. 2008;143: Loirat C, Frémeaux-Bacchi V. Orphanet J Rare Dis. 2011;6: Gastoldi S, Noris M, Macor P, et al. Immunobiology. 2012;217: Salant DJ. J Am Soc Nephrol. 2011;22:7-9.

13. Chronic, Uncontrolled Complement Activity Results in Continuous Endothelial Damage and Ongoing Risk of TMA1
Elevated Baseline Complement Activity
Chronic Complement Activity
Complement-Mediated TMA
Disrupted endothelial cells:
Release complement- activating microparticles, resulting in a vicious cycle of endothelial activation, complement amplification, and ongoing endothelial injury2,3
Release pro-thrombotic coagulation proteins, activate platelets, and recruit leukocytes, resulting in the formation of thrombi in small blood vessels throughout the body2
red blood cell
leukocyte
platelet
activated leukocyte
activated platelet
vWF
prothrombotic factors
schistocyte
Footnotes: vWF = Von Willebrand Factor; Image for illustrative purposes only, objects are not to scale. References: 1. Noris M and Remuzzi G Nat Rev Nephrol. 2014;10(3): Noris M, Mescia F, Remuzzi G. Nat Rev Nephrol. 2012;8: Renner B, Klawitter J, Goldberg R, et al. J Am Soc Nephrol. 2013;24:

14. Chronic, Uncontrolled Complement Activity Results in Continuous Endothelial Damage and Ongoing Risk of TMA1
Elevated Baseline Complement Activity
Chronic Complement Activity
Complement-Mediated TMA
Ischemia
Progressive Organ Damage
red blood cell
leukocyte
platelet
activated leukocyte
activated platelet
vWF
prothrombotic factors
schistocyte
Uncontrolled complement activity causes ongoing vascular endothelial injury2-5
Resulting TMA lesions may progress toward irreversible multi-organ damage2-5
Footnotes: vWF = Von Willebrand Factor; Image for illustrative purposes only, objects are not to scale. References: 1. Noris M and Remuzzi G Nat Rev Nephrol. 2014;10(3): Laurence J. Clin Adv Hematol Oncol. 2012;10(suppl 17): Legendre CM, Licht C, Muus P, et al. N Engl J Med. 2013;368: Sellier-Leclerc A-L, Frémeaux-Bacchi V, Dragon-Durey MA, et al;French Society of Pediatric Nephrology. J Am Soc Nephrol. 2007;18: Nester CM, Thomas CP. Hematology Am Soc Hematol Educ Program. 2012;2012:

15. Systemic, Complement-Mediated TMA Affects Multiple Vital Organs and Tissues1-16
Renal: More than 50% of patients progress to ESRD1
Elevated creatinine2,3
Proteinuria4
Oedema,3 malignant hypertension5
Decreased eGFR6
CNS: Up to 48% of patients experience neurological symptoms4
Confusion7
Stroke7
Encephalopathy5
Seizure4
Blood:
Thrombocytopenia1
Decreased haptoglobin1
Elevated LDH1
Decreased haemoglobin1
Schistocytes1
Visual:
Ocular occlusion8
Cardiovascular: Up to 43% of patients experience cardiovascular symptoms4
Myocardial infarction9,16
Hypertension10
Diffuse vasculopathy6
Peripheral gangrene11,16
Gastrointestinal: 37% of patients experience GI symptoms12
Diarrhoea13
Colitis7
Nausea/Vomiting14
Pancreatitis14
Abdominal pain7
Gastroenteritis5
Liver necrosis6
Pulmonary:
Dyspnea9
Pulmonary haemorrhage15
Pulmonary oedema9
A full clinical assessment should evaluate multiple organ systems
References: 1. Caprioli J, Noris M, Brioschi S,et al; for the International Registry of Recurrent and Familial HUS/TTP. Blood. 2006;108: Ariceta G, Besbas N, Johnson S, et al; for the European Paediatric Study Group for HUS. Pediatr Nephrol. 2009;24: Ståhl A-L, Vaziri-Sani F, Heinen S, et al.. Blood. 2008;111: Neuhaus TJ et al. Arch Dis Child. 1997;76: Noris M et al. Clin J Am Soc Nephrol. 2010; 5: Loirat C et al. Pediatr Nephrol. 2008;23: Ohanian M et al. Clin Pharmacol. 2011;3: Larakeb A et al. Pediatr Nephrol. 2007;22: Sallée M et al. Nephrol Dial Transplant. 2010;25: Kavanagh D et al. Med Bull. 2006;77-78: Malina M et al. Pediatr Nephrol. 2011;26: Langman C. Haematologica. 2012;97(s1): Zuber J et al. Nat Rev Nephrol. 2011;7: Dragon-Durey M-A et al. J Am Soc Nephrol. 2010;21: Sellier-Leclerc A-L al; French Society of Pediatric Nephrology. J Am Soc Nephrol. 2007;18: Noris M and Remuzzi G Nat Rev Nephrol. 2014;10(3):

16. Complement-Amplifying Conditions Place Patients with aHUS at
High Risk for TMA Manifestations

17. More Frequent Conditions Less Frequent Conditions
Complement-Amplifying Conditions Place Patients with aHUS at High Risk for Unpredictable TMA Manifestations1-4
Complement amplification occurs frequently and is not always apparent2,5-7
More Frequent Conditions
Less Frequent Conditions
Diarrhoea/Gastroenteritis
Bacterial, viral, and fungal infections
Atherosclerosis
Pregnancy-associated
Surgeries
Allergies
Asthma
Anaphylactic shock
Malignant Hypertension
Transplant-Associated
Inflammatory Bowel Disease
Glomerulopathy
Systemic Disease*
Malignancy
Thyroiditis
*Systemic Lupus Erythematosus or Scleroderma.
References: 1. Noris M, Mescia F, Remuzzi G. Nat Rev Nephrol. 2012;8: Liszewski MK, Atkinson JP. Hematology Am Soc Hematol Educ Program. 2011;2011: Fang CJ, Richards A, Liszewski MK, et al. Br J Haematol. 2008;143: Campistol JM, Arias M, Ariceta G, et al. Nefrologia. 2013;33: Hirt-Minkowski P, Dickenmann M, Schifferli JA. Nephron Clin Pract. 2010;114:c219-c Ricklin D, Hajishengallis G, Yang K, et al. Nat Immunol. 2010;11: Wagner E, Frank MM. Nat Rev Drug Discov. 2010;9:43-56.

18. aHUS can be Unmasked by Complement-Amplifying Conditions1
Complement-amplifying conditions present a situation where aHUS can be identified in patients who may otherwise go undiagnosed1
Patients with aHUS are particularly susceptible to TMA when experiencing a complement-amplifying condition2-6
Amplification of complement in patients with aHUS can upregulate the complement cascade beyond the patient’s ability to regulate
References: 1. Noris M, Caprioli J, Bresin E, et al. Clin J Am Soc Nephrol. 2010;5: Noris M, Mescia F, Remuzzi G. Nat Rev Nephrol. 2012;8: Frémeaux-Bacchi V, Fakhouri F, Garnier A, et al. Clin J Am Soc Nephrol. 2013;8: Liszewski MK, Atkinson JP. Hematology Am Soc Hematol Educ Program. 2011;2011: Fang CJ, Richards A, Liszewski MK, et al. Br J Haematol. 2008;143: Campistol JM, Arias M, Ariceta G, et al. Nefrologia. 2013;33:27-45.

19. 69% of Patients with aHUS Showed their First Clinical Manifestation While Experiencing One of the Following Complement-Amplifying Conditions (N=191*)1
More Frequent Conditions
Less Frequent Conditions
Diarrhoea/
Gastroenteritis 24%
Upper respiratory tract
infections 18%
Malignant hypertension 8%
Pregnancy Associated 7%
Malignancy 1%
Others 12%
Footnotes: *Patients with non-familial aHUS **E.g., Systemic Lupus Erythematosus and Scleroderma.
Reference: 1. Noris M, Caprioli J, Bresin E, et al. Clin J Am Soc Nephrol. 2010;5:

20. aHUS Can Be Unmasked by Pregnancy-Associated Complement Amplification

21. aHUS Associated with Pregnancy Can Lead to Significant and Rapid Onset of Renal Damage1
21% (21/100) of female patients with aHUS presented with TMA during pregnancy or post-partum in a national aHUS registry1
81% (17/21) of patients required haemodialysis1
62% (13/21) of female patients with aHUS reached ESRD within the first month after TMA manifestation1
Patients with ESRD
Reference: 1. Fakhouri, et al. Pregnancy-Associated haemolytic uraemic Syndrome Revisited in the Era of Complement Gene Mutations. J Am Soc Nephrol

22. Chronic, Uncontrolled Complement Activity Resulting From aHUS is a Known Cause of Pregnancy-Associated TMA1-2
aHUS shared common clinical features with other pregnancy- associated complications and may be underdiagnosed
aHUS complement mutations have been identified in 5-15% of preeclampsia cases and in a higher percentage of HELLP cases1
aHUS is commonly unmasked post-partum, while TMA due to severe ADAMTS13 deficiency occurs more often during pregnancy2
79% of the pregnancy-associated aHUS diagnoses presented in the post-partum period2
History of a normal first pregnancy does not exclude a diagnosis of aHUS2
57% (12/21) of patients first presented with aHUS unmasked during a second or subsequent pregnancy2
Reference: 1. Liszewski MK, Atkinson JP. Hematology Am Soc Hematol Educ Program. 2011;2011: Fakhouri, et al. Pregnancy-Associated haemolytic uraemic Syndrome Revisited in the Era of Complement Gene Mutations. J Am Soc Nephrol

23. Malignant Hypertension (MHT)
aHUS Can Be Unmasked by
Malignant Hypertension (MHT)

24. Chronic, Uncontrolled Complement Activity Resulting from aHUS is a Known Cause of TMA in Patients with MHT1-2,5
Patients with severe or malignant hypertension and with an underlying complement mutation for aHUS are at high risk of TMA1-4
In MHT, complement activity can be amplified due to endothelial damage caused by shear stress and vasoconstriction5
TMA in patients with MHT or severe hypertension is associated with severe end organ damage6
86% of patients with MHT/severe hypertension and TMA did not recover normal renal function despite receiving antihypertensives in a retrospective analysis of 21 patients6
MHT is also a known complication of aHUS2,7,8
Reference: 1. Noris M, et al. Clin J Am Soc Nephrol Nadar SK, et al. J Human Hypertens ; 21: Totina A, et al. Clin Pediatr (Phila.) ;52: Noris M, et al. Nat Rev Nephrol ;8: Shibagaki Y, et al. Hypertens Res :28: Zhang B et al. Hypertens Res. 2008;31(3): Geerdink LM, et al. Pediatric Nephrol ;27: Barbour T, et al. Nephrol Dial Transplant ;27:

25. aHUS: Early Diagnosis is Critical to Improve Patient Outcomes

26. Definition of aHUS Signs and symptoms of complement-mediated TMA1
Decreased platelet count
Evidence of microangiopathic haemolysis
Evidence of organ impairment/damage (e.g. serum creatinine >ULN)
Differentiate from other TMA diseases1
ADAMTS13 Activity >5% → excludes severe ADAMTS13 deficiency (congenital or acquired TTP)
Absence of positive STEC test → excludes STEC as sole cause of TMA
No requirement for identified complement gene mutation
Genetic mutation cannot be identified in 30%-50% of patients with aHUS2,3
References: 1. Laurence J. Clin Adv Hematol Oncol. 2012;10 (10 Suppl 17): Kavangh D et.al Hematology Am Soc Hematol Educ Program. 2011;2011:15-20
3. Kavanagh D et al. British Medical Bulletin. 2006; 77 and 78: 5-22.

27. Challenges in Diagnosing aHUS
Clinical presentation can be similar to other systemic TMAs1
Complement-amplifying conditions may unmask aHUS2,4
Historical supportive care did not require differential diagnosis between aHUS, TTP, and STEC-HUS – historically grouped as TTP/HUS1,3
aHUS is a rare disease, leading to lack of clinical suspicion4
Advancements in management options warrant early diagnosis and intervention1,5
References: 1. Laurence J. Clin Adv Hematol Oncol. 2012;10 (10 Suppl 17): Noris M et al. N Engl J Med. 2009;361: Ariceta G et al. European Paediatric Study Group for HUS. Pediatr Nephrol. 2009;24: Kavanagh D et al. British Medical Bulletin. 2006; 77 and 78: Legendre CM, Licht C, Muus P, et al. N Engl J Med. 2013;368:

28. Differential Diagnosis for TMAs: aHUS, TTP and STEC-HUS
Thrombocytopenia1,2
Platelet count <150 x 109/L OR >25% Decrease from baseline1
Microangiopathic Hemolysis2,3
Schistocytes2,3 and/or Elevated LDH2 and/or Decreased haptoglobin2 and/or Decreased haemoglobin2
AND
AND
Plus 1 or more of the following:
Neurological Symptoms4-7
Confusion4,5 and/or Seizures6 and/or Other cerebral abnormalities5
Renal Impairment2,9,10
Elevated creatinine10 and/or Decreased eGFR2,10 and/or Elevated blood pressure11 and/or Abnormal urinalysis9
Gastrointestinal Symptoms2,6,12
Diarrhea +/– blood12 and/or Nausea/vomiting6 and/or Abdominal pain6 and/or Gastroenteritis2,12
Evaluate ADAMTS13 activity and Shiga-toxin/EHEC* test8,13–15
While waiting for ADAMTS13 results, a platelet count >30 x109/L or serum creatinine >150–200 µmol/L (>1.7–2.3 mg/dL) almost eliminates a diagnosis of severe ADAMTS13 deficiency (TTP)16,17
A patient with a TMA presenting with SCr >1.7 mg/dL OR platelet count >30 x 109/L is less likely to have severe ADAMTS13 deficiency (TTP) than those who meet neither criteria 1,17
This pathway is intended as educational information for healthcare providers. It does not replace a healthcare professional’s judgment or clinical diagnosis.
Footnotes: *Shiga-toxin/EHEC test is warranted with history/presence of GI symptoms. References: 1. Data on file. Alexion Pharmaceuticals, Inc. 2. Caprioli J et al. Blood. 2006;108(4): Noris M et al. NEJM. 2009;361: Neuhaus et al. Arch Dis Chilid. 1997;76: Noris M et al. JASN. 2005;16: Dragon-Durey et al. J Am Soc Nephrol. 2010;21: Davin et al. Am J Kid Dis. 2010;55: ; 8. Bianchi et al. Blood. 2002;110: Al-Akash et al. Pediatr Nephrol. 2011;26: Sellier-Leclerc AL. JASN. 2007;18: Benz et al. Curr Opin Nephrol Hypertens. 2010;19: Noris M et al. Clin J Am Soc Nephrol. 2010;5: Tsai H-M. Int J Hematol. 2010;91:1-19; 14. Barbot et al. Br J Haematol. 2001;113: Bitzan M. Semin Thromb Hemost. 2010;36: Zuber J et al. Nat Rev Nephrol. 2012;8: Coppo P, Schwarzinger M, Buffet M, et al. PLOS ONE. 2010;5:e10208.

29. Differential Diagnosis for TMAs: aHUS, TTP and STEC-HUS
Thrombocytopenia1,2
Platelet count <150 x 109/L OR >25% Decrease from baseline1
Microangiopathic Hemolysis2,3
Schistocytes2,3 and/or Elevated LDH2 and/or Decreased haptoglobin2 and/or Decreased haemoglobin2
AND
AND
Plus 1 or more of the following:
Neurological Symptoms4-7
Confusion4,5 and/or Seizures6,8 and/or Other cerebral abnormalities5
Renal Impairment2,9,10
Elevated creatinine10 and/or Decreased eGFR2,10 and/or Elevated blood pressure11 and/or Abnormal urinalysis9
Gastrointestinal Symptoms2,6,12
Diarrhea +/– blood12 and/or Nausea/vomiting6 and/or Abdominal pain6 and/or Gastroenteritis2,12
Evaluate ADAMTS13 activity and Shiga-toxin/EHEC* test8,13–15
While waiting for ADAMTS13 results, a platelet count >30 x109/L or serum creatinine >150–200 µmol/L (>1.7–2.3 mg/dL) almost eliminates a diagnosis of severe ADAMTS13 deficiency (TTP)16,17
≤5% ADAMTS13 Activity8,13,14
>5% ADAMTS13 Activity8,12-14
Shiga-toxin/EHEC Positive15
TTP
aHUS
STEC-HUS
This pathway is intended as educational information for healthcare providers. It does not replace a healthcare professional’s judgment or clinical diagnosis.
Footnotes: *Shiga-toxin/EHEC test is warranted with history/presence of GI symptoms. References: 1. Data on file. Alexion Pharmaceuticals, Inc. 2. Caprioli J et al. Blood. 2006;108(4): Noris M et al. NEJM. 2009;361: Neuhaus et al. Arch Dis Chilid. 1997;76: Noris M et al. JASN. 2005;16: Dragon-Durey et al. J Am Soc Nephrol. 2010;21: Davin et al. Am J Kid Dis. 2010;55: ; 8. Bianchi et al. Blood. 2002;110: Al-Akash et al. Pediatr Nephrol. 2011;26: Sellier-Leclerc AL. JASN. 2007;18: Benz et al. Curr Opin Nephrol Hypertens. 2010;19: Noris M et al. Clin J Am Soc Nephrol. 2010;5: Tsai H-M. Int J Hematol. 2010;91:1-19; 14. Barbot et al. Br J Haematol. 2001;113: Bitzan M. Semin Thromb Hemost. 2010;36: Zuber J et al. Nat Rev Nephrol. 2012;8:

30. Patient/Family Medical History
Patient and Family Medical History May Help Determine if aHUS is the Underlying Cause of TMA1
Patient/Family Medical History
History of previous TMA
Unexplained renal failure
Malignant/severe hypertension
Unexplained MI
Preeclampsia with renal involvement that persisted after pregnancy
1. Noris M, et al. Clin J Am Soc Nephrol. 2010

31. No Requirement for Genetic Testing in the Diagnosis of aHUS
Genetic mutation cannot be identified in 30%-50% of patients with aHUS1,2
No requirement for identified complement gene mutation
Results generally take weeks to months – therefore, does not impact initial clinical management
Regardless of whether or not a mutation is identified, patients with aHUS have similarly devastating outcomes3
References: 1.Kavangh D et.al Hematology Am Soc Hematol Educ Program. 2011;2011: Kavanagh D et al. British Medical Bulletin. 2006; 77 and 78: Noris M, et al. Clin J Am Soc Nephrol. 2010;5:

32. No Requirement for Complement Level Testing in the Diagnosis of aHUS
Complement and soluble complement regulatory protein levels in plasma or serum are unreliable in the diagnosis of aHUS1,2
Majority of aHUS patients have normal levels of complement2
Serum C3 – normal in approximately 80% of aHUS patients
References: 1. Noris M, et al. Clin J Am Soc Nephrol. 2010;5: Laurence J. Clin Adv Hematol Oncol. 2012;10 (10 Suppl 17):1-12.

33. Historical Supportive Care Options
Limitations of
Historical Supportive Care Options

34. Historical Supportive Care Options for aHUS Fail to Address Underlying Chronic Uncontrolled Complement Activity1-13
PE/PI
Serious complications in children (55%) and adults (15%)1
26% of all patients experience major complications, including death, systemic infection, thrombosis, and pulmonary haemorrhage2
Dialysis
The overall five-year mortality rate for dialysis and peritoneal dialysis patients was 54%3
Does not protect patients from serious, extra renal morbidities, including thrombocytopenia, haemolysis, cerebral ischemic events, ocular damage, peripheral gangrene, vascular stenoses and arterial steno-occlusive lesions4-8
Kidney Transplant9,10
Liver Kidney Transplant
High risk of morbidity and mortality11
Antihypertensives12,13
Packed Red Blood Cell Transfusions12,13
References: 1. Zuber J et al. Nat Rev Nephrol. 2012;8: Nguyen L et al. Transfusion. 2009;49: Australian Institute of Health and Welfare. Dialysis and kidney transplantation in Australia: 1991–2010. Cat. no. PHE 162. Canberra: AIHW.4. Neuhaus TJ et al. Arch Dis Child. 1997;76: Malina M et al. Pediatr Nephrol. 2011;26: Larekeb A et al. Pediatr Nephrol. 2007;22: ; 7. Remuzzi G et al. Am J Transplant. 2005;5: Vergouwen MDI et al. AJNR Am J Neuroradiol. 2008;29:e Bresin E et al. International Registry of Recurrent and Familial HUS/TTP. Clin J Am Soc Nephrol. 2006;1:88-99; 10. Davin JC et al. Am J Kidney Dis. 2010;55: Saland, New York - 5 cases; Lorait 2011 Orphanet; Zuber 2012, and Nester. 12. Ariceta G et al. Pediatr Nephrol. 2009;24: Waters AM et al. Pediatr Nephrol. 2011;26:41-57.

35. Summary
In aHUS, 79% of patients die, require dialysis, or have permanent renal damage within 3 years1
33 to 40% of patients die or progress to end-stage renal disease with the first clinical manifestation, despite PE/PI1,2
Chronic, uncontrolled complement activity results in continuous endothelial and tissue injury
Complement amplification is common, unpredictable and puts patients at constant risk of sudden death and multi-organ damage
aHUS should be suspected in patients presenting with both a complement-amplifying condition and TMA
ADAMTS13 activity, serum creatinine levels and platelet count can be used to exclude a diagnosis of severe ADAMTS13 deficiency (TTP)
Advancements in treatment options warrant early diagnosis and ongoing intervention
References: 1. Noris M, Caprioli J, Bresin E, et al. Clin J Am Soc Nephrol. 2010;5: Caprioli J, Noris M, Brioschi S, et al; for the International Registry of Recurrent and Familial HUS/TTP. Blood. 2006;108:

36. aHUS Registry Registry Inclusion Criteria Exclusion Criteria
Observational, non-interventional, multinational
Patients with a diagnosis of aHUS, regardless of treatment, will be eligible for enrollment after providing written, informed consent
Inclusion Criteria
Male or female patients of any age, including minors, who have been diagnosed with aHUS
Diagnosis of aHUS includes:
Clinical diagnosis of aHUS
Patients with or without an identified complement regulatory factor genetic abnormality or anti-complement factor antibody
Exclusion Criteria
Patients with haemolytic uraemic syndrome (HUS) only due to Shiga-toxin are excluded
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