atypical hemolytic uremic syndrome (ahus) · ahus is kidney failure.1-5 if ahus is suspected,...

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Alexion Corporate Communications. Updated June 2016. ATYPICAL HEMOLYTIC UREMIC SYNDROME (aHUS) CAUSES aHUS is caused by a genetic mutation in one or more complement regulatory genes, which results in uncontrolled and excessive activation of complement. 4,5,6 In healthy individuals, complement is used to attack foreign particles, and the system is highly regulated to prevent it from causing damage to tissues and organs. However, in patients with aHUS, when complement is activated, it cannot be controlled due to underlying genetic mutations. 4 CONSEQUENCES Patients with aHUS are at immediate and ongoing risk of the life- threatening and destructive consequences of complement- mediated TMA. 1,2,3 These complications can occur throughout the body, including the kidneys, brain, heart and other vital organs. 6,7 Among patients with aHUS: More than 50% experience impaired kidney function that leads to end-stage renal disease (ESRD) 6,8 48% experience neurological symptoms, including stroke and seizure 9,10 46% experience pulmonary symptoms, including dyspnea (trouble breathing) and pulmonary edema 11,12 43% experience cardiovascular symptoms, such as heart attack and high blood pressure 9,12,13 37% experience gastrointestinal complications such as diarrhea, colitis, nausea and vomiting 10,14,15,16 34% experience thrombosis outside of the kidneys 11 100% of patients in one study (n=30) experienced effects of aHUS in more than one organ system 11 Historically, 79% of all patients with aHUS have died, required kidney dialysis or had permanent kidney damage within three years after diagnosis despite plasma exchange/plasma infusion (PE/PI). 5 Moreover, 33% to 40% of patients die or progress to end- stage renal disease with the first clinical manifestation of aHUS despite PE/PI. 5,6 DIAGNOSIS aHUS can be difficult to diagnose; because the disease is so rare, many doctors have never encountered a case of it. Additionally, symptoms can vary from patient to patient, and some patients may not have symptoms for extended periods of time while others may feel sick frequently. 17,18 aHUS OVERVIEW Atypical hemolytic uremic syndrome (aHUS) is a genetic, chronic, ultra-rare disease that progressively damages the vital organs. 1,2 aHUS is caused by chronic, uncontrolled activation of complement, a part of the body’s natural immune system, resulting in complement-mediated thrombotic microangiopathy (TMA)—the formation of blood clots in small blood vessels throughout the body. 1-4 TMA can lead to stroke, heart attack, kidney failure and premature death. aHUS affects both adults and children. In a large group of aHUS patients, about 60% were diagnosed under the age of 18. 5 US/UNB-AHUS/16/0075

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Page 1: ATYPICAL HEMOLYTIC UREMIC SYNDROME (aHUS) · aHUS is kidney failure.1-5 If aHUS is suspected, laboratory tests should be conducted to measure red blood cell and platelet counts, as

Alexion Corporate Communications. Updated June 2016.

ATYPICAL HEMOLYTIC UREMIC SYNDROME (aHUS)

CAUSES

aHUS is caused by a genetic mutation in one or more complement regulatory genes, which results in uncontrolled and excessive activation of complement.4,5,6 In healthy individuals, complement is used to attack foreign particles, and the system is highly regulated to prevent it from causing damage to tissues and organs. However, in patients with aHUS, when complement is activated, it cannot be controlled due to underlying genetic mutations.4

CONSEQUENCES

Patients with aHUS are at immediate and ongoing risk of the life-threatening and destructive consequences of complement- mediated TMA.1,2,3 These complications can occur throughout the

body, including the kidneys, brain, heart and other vital organs.6,7

Among patients with aHUS:

More than 50% experience impaired kidney function that leads to end-stage renal disease (ESRD)6,8

48% experience neurological symptoms, including stroke and seizure9,10

46% experience pulmonary symptoms, including dyspnea (trouble breathing) and pulmonary edema11,12

43% experience cardiovascular symptoms, such as heart attack and high blood pressure9,12,13

37% experience gastrointestinal complications such as diarrhea, colitis, nausea and vomiting10,14,15,16

34% experience thrombosis outside of the kidneys11

100%ofpatientsinonestudy(n=30)experiencedeffects of aHUS in more than one organ system11

Historically, 79% of all patients with aHUS have died, required kidney dialysis or had permanent kidney damage within three years after diagnosis despite plasma exchange/plasma infusion (PE/PI).5 Moreover, 33% to 40% of patients die or progress to end-stagerenaldiseasewiththefirstclinicalmanifestationofaHUSdespite PE/PI.5,6

DIAGNOSIS

aHUScanbedifficulttodiagnose;becausethediseaseissorare,many doctors have never encountered a case of it. Additionally, symptoms can vary from patient to patient, and some patients may not have symptoms for extended periods of time while others may feel sick frequently.17,18

aHUS OVERVIEW

Atypical hemolytic uremic syndrome (aHUS) is a genetic, chronic, ultra-rare disease that progressively damages the vital organs.1,2 aHUS is caused by chronic, uncontrolled activation of complement, a part of the body’s natural immune system, resulting in complement-mediated thrombotic microangiopathy (TMA)—the formation of blood clots in small blood vessels throughout the body.1-4 TMA can lead to stroke, heart attack, kidney failure and premature death. aHUS affects both adults and children. In a large group of aHUS patients, about 60% were diagnosed under the age of 18.5

US/UNB-AHUS/16/0075

Page 2: ATYPICAL HEMOLYTIC UREMIC SYNDROME (aHUS) · aHUS is kidney failure.1-5 If aHUS is suspected, laboratory tests should be conducted to measure red blood cell and platelet counts, as

Alexion Corporate Communications. Updated June 2016. ALEXION.COM

Initial signs and symptoms of aHUS include confusion, stomach pain, vomiting and diarrhea. One of the most common signs of aHUS is kidney failure.1-5 If aHUS is suspected, laboratory tests should be conducted to measure red blood cell and platelet counts, as well as creatinine levels. If red blood cell and platelet counts are low and creatinine levels are elevated, it may be a sign of aHUS.1,6

Although50%to70%ofpatientswithaconfirmeddiagnosisofaHUShaveidentifiablegeneticmutations,genetictestingisnotrequired for diagnosis.13,19

aHUS shares symptoms with two diseases, thrombotic thrombocytopenic purpura (TTP) and Shiga toxin E. coli-related hemolytic uremic syndrome (STEC-HUS). Laboratory tests can helpdifferentiateaHUSfromthesetwodiseases.UnlikeaHUS,TTP is an autoimmune disorder caused by low levels of a protein called ADAMTS13 in the blood. If a patient has less than 5% of normal ADAMTS13 levels, he or she is likely to have TTP, not aHUS.20 STEC-HUS results from an isolated episode of infection. Patients who have gastrointestinal symptoms such as diarrhea can be tested for STEC-HUS using a stool sample. However, it’s possible to have both aHUS and STEC-HUS, so a patient who tests positive for STEC-HUS may be monitored for signs of aHUS.8,21

US/UNB-AHUS/16/0075

DISEASE MANAGEMENT

Disease management approaches such as plasma therapy, dialysis orkidneytransplantdonotspecificallytargetuncontrolledcomplement activation, the underlying cause of TMA in patients withaHUS,andhavebeenproventobeclinicallyineffective.1,5,6

In recent years, increased understanding of the role of complement in the pathophysiology of aHUS has led to major advances in diagnosing and caring for patients with the disease. An early and accurate diagnosis and ongoing care are critical because patients with aHUS are at ongoing risk of sudden, catastrophic, and life-threatening symptoms and complications.1,2

To learn more about aHUS, visit aHUSsource.com.

Page 3: ATYPICAL HEMOLYTIC UREMIC SYNDROME (aHUS) · aHUS is kidney failure.1-5 If aHUS is suspected, laboratory tests should be conducted to measure red blood cell and platelet counts, as

Alexion Corporate Communications. Updated June 2016. ALEXION.COM

1. Laurence J. Atypical hemolytic uremic syndrome (aHUS): making the diagnosis. ClinAdvHematolOncol.2012;10(suppl17):1-12.

2. Campistol JM, Arias M, Ariceta G, et al. An update for atypical haemolytic uraemic syndrome:diagnosisandtreatment.Nefrologia.2013Jan18;33(1):27-45.

3. Sellier-LeclercA-L,Frémeaux-BacchiV,Dragon-DureyMA,etal;FrenchSocietyofPediatricNephrology.Differentialimpactofcomplementmutationsonclinicalcharacteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2007;18:2392-2400.

4. Noris M, Mescia F, Remuzzi G. STEC-HUS, atypical HUS and TTP are all diseases ofcomplementactivation.NatRevNephrol.2012;8:622-633.

5. Noris M, Caprioli J, Bresin E, et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype.ClinJAmSocNephrol.2010;5:1844-1859.

6. CaprioliJ,NorisM,BrioschiS,etal;fortheInternationalRegistryofRecurrent and Familial HUS/TTP. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood. 2006;108:1267-1279.

7. Hirt-MinkowskiP,DickenmannM,SchifferliJA.Atypicalhemolyticuremicsyndrome: update on the complement system and what is new. Nephron Clin Pract. 2010;114:c219-c235.

8. AricetaG,BesbasN,JohnsonS,etal;TheEuropeanPaediatricStudyGroupforHUS.Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremicsyndrome.PediatrNephrol.2009;24:687-696.

9. Neuhaus TJ, Calonder S, Leumann EP. Heterogeneity of atypical haemolytic uraemicsyndromes.ArchDisChild.1997;76:518-521.

10. OhanianM,CableC,HalkaK.ClinPharmacol.2011;3:5-12.

11. Muus P, Loirat C, Licht C, et al. Presented at: 18th Congress of the European HematologyAssociation.June13-16,2013;Stockholm,Sweden.AbstractB1774.

12. Sallee M, Daniel L, Piercecchi M-D, et al. Myocardial infarction is a complication offactorH-associatedatypicalHUS.NephrolDialTransplant.2010;25:2028-2032.

13. Kavanagh D, Goodship THJ, Richards A. Atypical haemolytic uraemic syndrome. BrMedBull.2006;77-78:5-22.

14. Langman C. Systemic multi-organ complications in atypical hemolytic uremic syndrome (aHUS): retrospective study in a medical practice setting. Haematologica. 2012;97(s1):195-196.

15. Zuber J, Le Quintrec M, Sberro-Soussan R, Loirat C, Fremeaux-Bacchi V, Legendre C. New insights into post-renal transplant hemolytic uremic syndrome. NatRevNephrol.2011;7:23-35.

16. Dragon-Durey M-A, Sethi SK, Bagga A, et al. Clinical features of anti-factor H autoantibody-associated hemolytic uremic syndrome. J Am Soc Nephrol. 2010;21:2180-2087.

17. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676-1687.

18. Loirat C, Garnier A, Sellier-Leclerc AL, Kwon T. Plasmatherapy in atypical hemolyticuremicsyndrome.SeminThrombHemost.2010;36:673-681.

19. Kavanagh D, Goodship THJ. Atypical hemolytic uremic syndrome, genetic basis, and clinical manifestations. Hematology Am Soc Hematol Educ Program. 2011;2011:15-20.

20. Tsai H-M. Pathophysiology of thrombotic thrombocytopenic purpura. IntJHematol.2010;91:1-19.

21. Bitzan M, Schaefer F, Reymond D. Treatment of typical (enteropathic) hemolytic uremicsyndrome.SeminThrombHemost.2010;36:594-610.

22. Sarode R, Bandarenko N, Brecher ME, et al. Thrombotic thrombocytopenic purpura: 2012 American Society for Apheresis (ASFA) consensus conference onclassification,diagnosis,management,andfutureresearch.JClinApher. 2013;DOI:10.1002/jca.21302.

References

US/UNB-AHUS/16/0075