1

Atypical Haemolytic Uraemic Syndrome (aHUS)Overview of Disease and Diagnosis MD NameTitle, Institution

2

• Chronic, progressive, risk of sudden death and vital organ damage1-4:

• 33-40% of patients die or progress to End Stage Renal Disease (ESRD) with the first clinical manifestation2,3

10-15% mortality in the initial phase3

– 19% mortality after initial manifestation in patients with CFH mutation3

• 65% of all patients die, require dialysis, or have permanent renal damage within the first year after diagnosis despite plasma exchange or plasma infusion (PE/PI)2

Atypical Haemolytic Uraemic Syndrome (aHUS):A Genetic, Devastating and Life-Threatening Disease

1. Sallee M, et al. Nephrol Dial Transplant. 2010;25:2028-2032. 2. Caprioli J et al Blood. 2006; 108:1267-1272. 3. Noris M, et al. Clin J Am Soc Nephrol. 2010;10:1844-1859. 4. Noris M, et al. N Engl J Med. 2009;361:1676-1687.

Significant morbidity and mortality within 1 year2

0.00

0.25

0.50

0.75

1.00

Cum

ulat

ive

Frac

tion

of

CFH

Pat

ient

s Fr

ee o

f Eve

nts

0 3 6 12.5 25Follow-up After Initial Onset (Months)

Modified from Caprioli et al, 2006. Data show patients with CFH mutations. CFH mutations=most common mutations.

70% of patients with CFH mutation (the most common mutation)died, required dialysis, orhad permanent renaldamage within 1 year2

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aHUS: Complement-Mediated Thrombotic Microangiopathy (TMA)

• 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

• Coexisting diseases or conditions may unmask aHUS4

• Affects both adults and children2

1. Noris M et al. N Engl J Med. 2009;361:1676-1687; 2. Noris M et al. Clin J Am Soc Nephrol 2010;5:1844–1859; 3. Desch K et al. JASN 2007;18:2457-2460; 4. Kavanagh D et al. British Medical Bulletin 2006; 77 and 78: 5–22.

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The Role of Complement in aHUS

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The Complement System: Always on, Strongly Amplified, Dependent on Natural Regulators

The complement system is a vital component of the innate protective immune system1

• Complement is activated by three mechanisms (classical, alternative, and lectin) which allow the system to respond to inflammatory, infectious, ischaemic, necrotic insult, as well as foreign and self antigens

• Always ‘on’ to allow rapid immune response1

– Rapid amplification leads to powerful and destructive immune reactions2

– Natural inhibitors of complement keep amplification in check and prevent uncontrolled complement activation2

1. Holers VM et al. Immunol Rev 2008;223:300–316; 2. Zipfel PF et al. Curr Opin Nephrol Hypertens 2010;4:372–378.

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Factors That Amplify Complement Activation

Glovsky MM et al. Ann Allergy Asthma Immunol 2004;93:513–523; Rubio MT et al. Bone Marrow Transplant 2008;41(Suppl. 1):S220. Abstract P766; Mastellos D et al. Immunologic Res 2003;3:367–385; Mergenhagen STE et al. J Infect Dis 1973;128:S86; Chenoweth DE et al. N Engl J Med 1981;304:497–503; Giradi G. Am J Reprod Immunol 2008;59:183–192.

Infection Surgery

Autoimmune Pregnancy

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AnaphylaxisInflammationThrombosis

ConsequencesCell destruction

InflammationThrombosis

Consequences

C5a

• Potent anaphylatoxin• Chemotaxis• Pro-inflammatory• leucocyte activation• Endothelial activation• Pro-thrombotic

C5b-9Membrane attack complex

• Cell lysis• Pro-inflammatory • Platelet activation• leucocyte activation• Endothelial activation• Pro-thrombotic

C5C5b

C6C7C8 C9

1. Zipfel PF et al. Vaccine 2008;26(Suppl 8):I67–74; 2. Figueroa JE, Densen P. Clin Microbiol Rev 1991;4:359–395; 3. Walport MJ. N Engl J Med 2001;344:1058–1066; 4. Rother RP et al. Nat Biotechnol 2007;25:1256–1264; 5. Meyers G et al. Blood 2007;110:abs 3683; 6. Hill A et al. Br J Haematol 2010;149:414–425; 7. Hillmen P et al. Am J Hematol. 2010;85:553–559; 8. Parker C et al. Blood 2005;106:3699–3709; 9. Hillmen P et al. N Engl J Med 1995;333:1253–1258; 10. Nishimura J et al. Medicine (Baltimore) 2004;83:193–207; 11. Caprioli J et al. Blood 2006;108: 1267–1279; 12. Noris M et al. Clin J Am Soc Nephrol 2010;5:1844–1859; 13. George JN. Blood 2010;116:4060–4069; 14. Loirat C et al. Pediatr Nephrol 2008;23:1957–1972; 15. Ståhl AL et al. Blood 2008;111:5307–5315; 16. Hosler GA et al. Arch Pathol Lab Med 2003;127;834–839; 17. Ariceta G et al. Pediatr Nephrol. 2009;24:687–696.

Chronic Uncontrolled Complement Activation Leads to Devastating Consequences in aHUS

Natural Inhibitors: Factor H, I, MCP−

Thrombomodulin−

Prox

imal

Term

inal

Lectin Pathway Classical Pathway Alternative Pathway

Immune complex clearanceMicrobial opsonisation

C5-convertase

C3a

C3

C3bWeak anaphylatoxin

C3 + H2O: always active (chronic)Amplification

Gain of Function Mutations: C3, CFB

+

7

iC3b

8

Ongoing Research in the Field of Complement Inhibitors• Most genetic mutations have been discovered in the past 20 years1

• 30–50% of patients with aHUS have no identifiable genetic mutation2

1. Timeline adapted from: Le Quintrec M et al. Semin Thromb Hemost 2010;36:641–665; 2. Noris M et al. Clin J Am Soc Nephrol 2010;5:1844–1859.

Link with low C3

Homozygous CFH deficiency

CFI mutations

C3 mutationsLink with RCA – CFH mutations

(SCR20) Thrombomodulin mutations

Hybrid (CFH-CFHRI)

Heterozygous CFH deficiency

Association with low CFH MCP mutations

Anti-FH auto-antibodies

Homozygous MCP deficiency

CFB mutations

1973 1981 1994 1998 2003 2004 2005 2006 2007 2009

DCFHR1/DCFHR3 deletion

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Endothelial cells: - Activation - Swelling and disruption

Platelets:- Activation- Aggregation

leucocytes:- Activation

Platelet consumptionMechanical haemolysis

Blood clotting Vessel occlusion

Inflammationischaemia

Systemic multi-organ complications

Clinical consequences:

Red cells:-haemolysis

Modified by Zipfel and Jokiranta from Desch et al. JASN 2007;18:2457–6240; Licht C et al. Blood 2009 114:4538–4545; Noris M et al. NEJM 2009;361:1676–687; Stahl A et al. Blood 2008;111:5307–5315; Morigi et al. J Immunol 2011

Uncontrolledcomplement

activation on cells

Chronic Uncontrolled Complement Activation Leads to Endothelial and End Organ Damage

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RenalMore than 50% of patients progress to ESRD7

• Elevated creatinine• Proteinuria2

• Oedema,3 malignant hypertension4

• Decreased eGFR5

CNSUp to 48% of patients experience neurological symptoms2

• Confusion6

• Stroke6

• Encephalopathy4

• Seizure2

CardiovascularUp to 43% of patients experiencecardiovascular symptoms2

• Myocardial infarction8

• Hypertension9

• Diffuse vasculopathy5

• Peripheral gangrene10

GastrointestinalUp to 30% of patientspresent with diarrhoea11

• Colitis6

• Nausea/Vomiting12

• Pancreatitis12

• Abdominal pain6

• Gastroenteritis2

• Liver necrosis2Blood• Thrombocytopenia7

• Decreased haptoglobin7

• Elevated LDH7

• Decreased haemoglobin7

• Schistocytes7

Pulmonary• Dyspnoea8

• Pulmonary haemorrhage13 • Pulmonary oedema8

1. Ariceta G et al. European Paediatric Study Group for HUS. Pediatr Nephrol 2009;24:687–696; 2. Neuhaus TJ et al. Arch Dis Child 1997;76:518–521. 3. Ståhl A-L et al. Blood 2008;111:5307–5315. 4. Noris M et al. Clin J Am Soc Nephrol 2010;5:1844–1859; 5. Loirat C et al. Pediatr Nephrol 2008;23:1957–1972; 6. Ohanian M et al. Clin Pharmacol 2011;3:5–12 ;7. Caprioli J et al. Blood 2006;108:1267–1279; 8. Sallée M et al. Nephrol Dial Transplant 2010;25:2028–2032; 9.Kavanagh D et al. Med Bull 2006;77–78:5–22; 10. Malina M et al. Pediatr Nephrol 2011;26:1678; 11. Zuber J et al. Nat Rev Nephrol 2011;7:23–35; 12. Dragon-Durey M-A et al. J Am Soc Nephrol 2010;21:2180–2187; 13.Sellier-Leclerc A-L al; French Society of Pediatric Nephrology. J Am Soc Nephrol 2007;18:2392-2400; 14. Larakeb A et al. Pediatr Nephrol 2007;22:1967–1970.

Systemic, Complement-mediated TMA AffectsMultiple Vital Organs and Tissues

Visual • Ocular occlusion14

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aHUS: More than a Renal DiseasePresence of aHUS Complications by System¹

1. Langman C et al. Systemic Multi-Organ Complications in Atypical haemolytic uraemic Syndrome (aHUS): Retrospective Study in a Medical Practice Setting. Poster 0490 presented at EHA 2012.

System Signs/Symptoms Number (%) of Patients with Complication

Renal Kidney impairment 30 (100%)

Cardiovascular Thrombi (various locations), cardiac arrest, cardiomyopathy

14 (47%)

Gastrointestinal Diarrhoea, vomiting, pancreatitis, splenic vein occlusion

11 (37%)

Neurologic Seizure, acute disseminated encephalomyelitis, stroke, transient ischaemic attacks, facial paralysis, headache

6 (20%)

aHUS complications in >1 system 19 (63%)

11 (37%) of the 30 aHUS patients experienced thrombi beyond the kidneyRetrospective chart review of 30 paediatric, adoloescent and adult aHUS patients who received eculizumab treatment between 2007 and 2009 outside of controlled clinical trial setting. Data corresponding to the time period prior to the first dose of eculizumab are described.

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PE/PI– No prospective controlled trials demonstrating efficacy of PE/PI in aHUS3

– Complications reported in children (55%) and adults (15%)1

– 26% of patients experienced major complications from PE, including death, systemic infection, thrombosis, and pulmonary haemorrhage (Source: Oklahoma TTP-HUS Registry)2

Dialysis– Does not protect patients from serious, extra renal morbidities, including thrombocytopenia,

haemolysis, cerebral ischaemic events, ocular damage, peripheral gangrene, vascular stenoses and arterial steno-occlusive lesions3–10

Kidney Transplant1

Liver-Kidney Transplant– Anecdotal reports; high risk of morbidity and mortality1,3,13,14

Antihypertensives11,12

Packed Red Blood Cell Transfusions11,12

1. Zuber J et al. Nat Rev Nephrol 2012;8:643–657; 2. Nguyen L et al. Transfusion 2009;49:392–394; 3. Loirat C et al. Semin Thromb Hemost 2010;36:673–681; 4. Neuhaus TJ et al. Arch Dis Child 1997;76:518–521; 5. Malina M et al. Pediatr Nephrol 2011;26:1678; 6. Larekeb A et al. Pediatr Nephrol 2007;22:1967–1970; 7. Remuzzi G et al. Am J Transplant 2005;5:1146–1150; 8. Vergouwen MDI et al. AJNR Am J Neuroradiol 2008;29:e34; 9. 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;55:708–711; 11. Ariceta G et al. Pediatr Nephrol 2009;24:687–696; 12. Waters AM et al. Pediatr Nephrol 2011;26:41–57; 13. . Nester C, et al. Clin J Am Soc Nephrol 2011; 14. Saland JM et al. J Am Soc Nephrol 2009;20:940–949.

Historical Care Options Fail to Address Underlying Chronic Uncontrolled Complement Activation

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Factors defining PE/PI failure after 5 daily plasma exchanges:• Platelet count and LDH are not normalized1,

• Serum creatinine is not reduced by at least 25%1

If TMA occurs in plasma dependent patients with detectable ADAMTS13 activity when withdrawing PE/PI, consider an alternative therapy

Zuber J et al. Nat Rev Nephrol. 2012 Nov;8(11):643-57.

Assessing PE/PI Failure: Recommendations from French study group for aHUS

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Affected Protein Outcome of Kidney Transplantation1

Factor H % of Patients with ongoing TMA: 80–90%

CFHR1, R3 % of Patients with ongoing TMA: 20%

MCP % of Patients with ongoing TMA: 15–20%

Factor I % of Patients with ongoing TMA: 70–80%

Factor B Ongoing TMA in 1 published case

C3 % of Patients with ongoing TMA: 40–50%

THBD Ongoing TMA in 1 published case

Kidney Transplant Does Not Address the Cause of aHUS

More than 90% of these patients experienced graft loss, mostly within the first year2

1. Noris M et al. N Engl J Med 2009;361:1676–1687;2. Bresin E et al. International Registry of Recurrent and Familial HUS/TTP. Clin J Am Soc Nephrol 2006;1:88–99.

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Liver-Kidney Transplant

• Procedure associated with a high risk of morbidity and mortality1

• Newly available alternative therapeutic options reduce the indications for combined liver-kidney transplant1

• Very few successful cases worldwide2

• Complex procedure performed at limited centres with expertise2

• Patients dependent on life-long immunosuppression with multiple drug treatments3

1. Zuber J, et al. Transplant Rev 2013; http://dx.doi.org/10.1016/j.trre.2013.07.003 2. Zuber J et al. Nat Rev Nephrol 2011;7:23–35. 3. Nester C, et al. Clin J Am Soc Nephrol 2011; 6(6):1488-94.

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aHUS: Early Diagnosis is Critical to Improve Patient Outcomes

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Challenges in Diagnosing aHUS

• Clinical presentation can be similar to other systemic TMAs1–4

• Historical treatment did not require differential diagnosis between aHUS, TTP, and STEC-HUS – historically grouped as TTP/HUS4,5

• aHUS is a rare disease, leading to lack of clinical suspicion6

Advancements in treatment options warrant early diagnosis and intervention

1. George et al. Blood 2010;116:4060–4069; 2. Noris M et al. N Engl J Med 2009;361:1676–1687; 3. Zipfel PF et al. Curr Opin Nephrol Hypertens 2010;19:372–378; 4. Bianchi et al. Blood 2002;100:710–713; 5. Loirat C et al. Semin Thromb Hemost 2010;36:673–681; 6. Ariceta G et al.; European Paediatric Study Group for HUS. Pediatr Nephrol 2009;24:687–696.

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Patients May Experience aHUS as a Single Disease or with Other Coexisting Diseases or ConditionsIn the International Registry of Recurrent and Familial HUS/TTP, 25% (47/191) of patients diagnosed with aHUS and no known affected family members had coexisting diseases:

Comorbid DiseasesaHUS Patients with Comorbid Disease,

n (%)Malignancy and chemotherapy 1 (2)

Malignant hypertension 14 (30)

Post-transplant HUS* and calcineurin inhibitors 11 (23)

Pregnancy-related HUS 10 (21)

Systemic disease Scleroderma Systemic Lupus Erythematosus (SLE)

3 (6)

Glomerulopathy† 8 (17)

Total 47 (100)*Primary cause of nephropathy unknown in 6 /11 pts (3 w/mutations): 2 IgA nephropathy, 1 diabetes mellitus nephropathy, 1 membranoproliferative glomerulonephritis, 1 reflux nephropathy.†Glomerulopathy: membranoproliferative glomerulonephritis, nephrotic syndrome, mesangioproliferative glomerulonephritis, membranous glomerulonephritis.Noris M et al. Clin J Am Soc Nephrol. 2010;5:1844-1859.

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TTP aHUS STEC-HUSSevere Deficiency (≤5%) of

ADAMTS13 ActivityGenetic, Complement

MediatedShiga-toxin Induced

Severely deficient (<5%) or no ADAMTS13 activity leaves

von Willebrand Factor (vWF) multimers uncleaved

Genetic defects in activators and/or inhibitors lead to chronic

uncontrolled activation of the complement system

Certain bacteria, notably E. coli produce toxins that

cause uncontrolled complement activation and direct cell

damage

Sources: Caprioli J et al. Blood 2006;108:1267–1279; Ariceta G et al. European Paediatric Study Group for HUS. Pediatr Nephrol 2009;24:687–696; 3. Sadler JE et al. Hematology Am Soc Hematol Educ Program 2004:407–423; Zheng XL. Blood 2010;115:1475–1476; Moake JL. N Engl J Med 2002;347:589–600; Ruggenenti P et al. Kidney Int 2001;60:831–846; Sadler JE. Blood 2008;112:11–18; Hirt-Minkowski P et al. Nephron Clin Pract 2010;114:c219–c235; Loirat C et al. Pediatr Nephrol 2008;23:1957–1972; Bitzan M et al. Semin Thromb Hemost 2010;36:594–610; Tsai HM. J Am Soc Nephrol 2003;14:1072–1081; Mayer SA, Aledort LM. Mt Sinai J Med 2005;72:166–175.

TMAs Often Share Similar Clinical Presentations But Differ in the Underlying Cause

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Tests for Differential Diagnosis

1. Zuber J et al. Nat Rev Nephrol 2012 Nov;8:643–657

ADAMTS13Test

Recommended in patients with TMA to differentiate aHUS from severe ADAMTS13 deficiency1

Shiga-Toxin Test

Recommended in patients with TMA and history/presence of GI symptoms to differentiate aHUS from STEC-HUS1

Clinical Assessment

While waiting for ADAMTS13 results:1

• Platelet count of >30 x 109/L • Serum creatinine level of >150–200 μmol/L almost eliminates

a diagnosis of severe ADAMTS13 deficiency

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Tests for Differential Diagnosis

*Genetic testing encompasses evaluation for genetic mutation, deletions, polymorphisms and antibody testing.

1. Zuber J et al. Nat Rev Nephrol 2011;7:23–35; 2. Noris M et al. Clin J Am Soc Nephrol 2010;5:1844–1859; 3. Loirat C et al. Pediatr Nephrol 2008;23:1957–1972; 4. Tsai H-M. Kidney Int 2006;70:16–23; 5. Benz K et al. Curr Opin Nephrol Hypertens 2010;19:242–247

Complement Level Test

• Complement mutation analysis is not indicated for aHUS diagnosis or initial treatment1*

• Results generally take weeks to months – therefore, does not impact initial clinical management1

• Genetic mutation cannot be identified in 30–50% of patients with aHUS2-5

Genetic Testing

• The majority of aHUS patients have normal levels of complement2

• Serum C3 – normal in many aHUS patients• Complement Factor H (CFH) protein levels – normal in

87% of aHUS patients with CFH mutation

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No Difference in Severity of Disease for Patients With an Identified Mutation Compared With Those With No Identifiable Mutation

Consequences No Identifiable Mutation

Identifiable Mutation

% of patients that died, required dialysis, or had permanent renal damage within the first year after diagnosis

65% 63%

% of patients that died or required dialysis long term 51% 57%

ESRD = end stage renal disease.

Caprioli J et al. Blood 2006;108:1267–1272.

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aHUS is a Clinical Diagnosis Supported by Appropriate Exclusion of Other TMAs

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aHUS: Complement-Mediated Thrombotic Microangiopathy (TMA)

Signs and symptoms of complement-mediated TMA1,2

• Decreased platelet count1

• Evidence of microangiopathic haemolysis1

• Evidence of organ impairment/damage (eg. serum creatinine >ULN)2,3

Differentiate from other TMA diseases1,2

• ADAMTS13 Activity >5% → excludes severe ADAMTS13 deficiency (congenital or acquired TTP)4,5,6,7

• Absence of positive STEC test → excludes STEC as sole cause of TMA8

No requirement for identified complement gene mutation• Genetic mutation cannot be identified in 30%-50% of patients with aHUS5

1. Davin et al. Am J Kid Dis. 2010;55(4):708-777. 2. Noris et al. JASN. 2005;16(5):1177-1183. 3. Dragon-Durey et al. J Am Soc Nephrol. 2010;21(12):2180-2187. 4. Sellier-Leclerc  AL, JASN. 2007;18:2392-2400. 5. Noris M, et al. Clin J Am Soc Nephrol. 2010;5:1844-1859. 6. Tsai H-M. Int J Hematol. 2010;91:1-19. 7. Lamelle et al. Haematologica. 2008;93(2):172-177. 8. Barbot et al. Brit J Haem. 2001;113(3):649.

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Plus One or More of the Following:

Differential Diagnosis for TMAs: aHUS, TTP and STEC-HUS

Evaluate ADAMTS13 activity and Shiga-toxin/EHEC* test8,13–15

Thrombocytopenia1,2

Platelet count <150,000 Or>25% Decrease from baseline1

Renal Impairment2,9,10

Elevated creatinine10 and/orDecreased eGFR2,10 and/or

Elevated blood pressure11 and/or Abnormal urinalysis9

Neurological Symptoms4-7

Confusion4,5 and/orSeizures6,8 and/or

Other cerebral abnormalities5

Gastrointestinal Symptoms2,6,12

diarrhoea +/– blood12 and/or Nausea/vomiting6 and/orAbdominal pain6 and/or

Gastroenteritis2,12

Microangiopathic haemolysis2,3

Schistocytes2,3 and/orElevated LDH2 and/or

Decreased haptoglobin2 and/orDecreased haemoglobin2

AND

This pathway is intended as educational information for healthcare providers. It does not replace a healthcare professional’s judgment or clinical diagnosis.

* Shiga-toxin/EHEC test is warranted with history/presence of GI symptoms.1. Data on file. Alexion Pharmaceuticals, Inc.; 2. Caprioli et al. Blood 2006;108:1267-7; 3. Noris M et al. NEJM 2009;361:1676–1687; 4. Neuhaus et al. Arch Dis Chilid 1997;76:518–521; 5. Noris M et al. JASN 2005;16:1177–1183; 6. Dragon-Durey et al. J Am Soc Nephrol 2010;21:2180–2187; 7. Davin et al. Am J Kid Dis 2010;55:708–777; 8. Bianchi et al. Blood 2002;110:710–713; 9. Al-Akash et al. Pediatr Nephrol 2011;26:613–619; 10. Sellier-Leclerc AL. JASN 2007;18:2392–2400; 11. Benz et al. Curr Opin Nephrol Hypertens 2010;19:242–247; 12. Noris M et al. Clin J Am Soc Nephrol 2010;5:1844–1859; 13. Tsai H-M. Int J Hematol 2010;91:1–19; 14. Barbot et al. Br J Haematol 2001;113:649; 15. Bitzan M. Semin Thromb Hemost 2010;36:594–610.

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*Adult patientsTable Adapted from Coppo P et al. PLoS ONE 5(4): e10208. doi:10.1371/journal.pone.00102081. Zuber J et al. Nat Rev Nephrol 2012 Nov;8:643–657

Patient Characteristics*

ADAMTS13Deficiency group

n=160

(standard deviation)

ADAMTS13Detectable group

n=54

(standard deviation)

P-Value

Platelet count, ×109/L 17.4 (14.2) 66.6 (49.3) <0.0001

Creatinine level, µmol/L 114 (68.4) 454 (326) <0.0001

Patient Characteristics* AdjustedOdds Ratio 95% CI P-Value

Platelet count ≤30×109/L 9.1 3.4–24.2 <0.001Creatinine level ≤200 µmol/L(2.26 mg/dL) 23.4 8.8–62.5 <0.001

While Waiting for ADAMTS13 results, a Platelet Count >30 x 109/L or Serum Creatinine >150–200 µmol/L Almost Eliminates a Diagnosis of Severe ADAMTS13 Deficiency (TTP)1

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Plus One or More of the Following:

Differential Diagnosis for TMAs: aHUS, TTP and STEC-HUS

STEC-HUSTTP aHUS

>5% ADAMTS13 Activity12≤5% ADAMTS13 Activity8,13,14 Shiga-toxin/EHEC Positive14

Evaluate ADAMTS13 activity and Shiga-toxin/EHEC* test8,13–15

Thrombocytopenia1,2

Platelet count <150,000 Or>25% Decrease from baseline1

Renal Impairment2,9,10

Elevated creatinine10 and/orDecreased eGFR2,10 and/or

Elevated blood pressure11 and/or Abnormal urinalysis9

Neurological Symptoms4-7

Confusion4,5 and/orSeizures6,8 and/or

Other cerebral abnormalities5

Gastrointestinal Symptoms2,6,12

Diarrhoea +/– blood12 and/or Nausea/vomiting6 and/orAbdominal pain6 and/or

Gastroenteritis2,12

Microangiopathic haemolysis2,3

Schistocytes2,3 and/orElevated LDH2 and/or

Decreased haptoglobin2 and/orDecreased haemoglobin2

AND

This pathway is intended as educational information for healthcare providers. It does not replace a healthcare professional’s judgment or clinical diagnosis.

* Shiga-toxin/EHEC test is warranted with history/presence of GI symptoms.1. Data on file. Alexion Pharmaceuticals, Inc.; 2. Caprioli et al. Blood 2006;108:1267-7; 3. Noris M et al. NEJM 2009;361:1676–1687; 4. Neuhaus et al. Arch Dis Chilid 1997;76:518–521; 5. Noris M et al. JASN 2005;16:1177–1183; 6. Dragon-Durey et al. J Am Soc Nephrol 2010;21:2180–2187; 7. Davin et al. Am J Kid Dis 2010;55:708–777; 8. Bianchi et al. Blood 2002;110:710–713; 9. Al-Akash et al. Pediatr Nephrol 2011;26:613–619; 10. Sellier-Leclerc AL. JASN 2007;18:2392–2400; 11. Benz et al. Curr Opin Nephrol Hypertens 2010;19:242–247; 12. Noris M et al. Clin J Am Soc Nephrol 2010;5:1844–1859; 13. Tsai H-M. Int J Hematol 2010;91:1–19; 14. Barbot et al. Br J Haematol 2001;113:649; 15. Bitzan M. Semin Thromb Hemost 2010;36:594–610; 16. Zuber J et al. Nat Rev Nephrol 2012 Nov;8:643–657.

While waiting for ADAMTS13 results, a platelet count >30 x 109/L or serum creatinine >150–200 µmol/L almost eliminates a diagnosis of severe ADAMTS13 deficiency (TTP)16

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aHUS RegistryRegistry• Observational, non-interventional, multinational • Patients with a diagnosis of aHUS, regardless of treatment, will be eligible

for enrollment after providing written, informed consentInclusion 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– ADAMTS13 >5% (if performed)

Exclusion Criteria• Patients with haemolytic uraemic syndrome (HUS) due to Shiga toxin

are excluded

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Summary

• aHUS causes sudden and progressive damage1,2

• aHUS is a chronic, genetic, life-threatening condition3–5

• aHUS has a systemic impact3

– 63% of aHUS patients have at least 1 complication outside of the kidney, including neurologic, cardiovascular, and gastrointestinal systems6

• aHUS affects both adults and children1 – Approximately half of patients are adults

• High clinical suspicion of aHUS is required in all patients presenting with TMA3

Advancements in treatment options warrant early diagnosis and intervention

1. Noris M et al. Clin J Am Soc Nephrol 2010;5:1844–1859; 2. Caprioli J et al. Blood 2006;108:1267–1279; 3. Loirat C. Pediatr Nephrol 2008;23:1957–1972; 4. Fang CJ et al. Br J Haematol 2008;143:336–348; 5. Hirt-Minkowski P et al. Nephron Clin Pract 2010;114:c219–c235; 6. Langman C. Presented at the 17th Congress of the European Hematology Association; June 14–17, 2012; Amsterdam, The Netherlands. Abstract 0490.

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Questions

© 2013 Alexion Pharmaceuticals Australasia Pty Limited. All rights reserved.Alexion Pharmaceuticals Australasia Pty Limited. ACN 132 343 036. Suite 401, Level 4, Building A. 20 Rodborough Road Frenchs Forest NSW 2086. Sep 2013. AU/SaHUS/13/0007