Natural complement regulators are required for control of the complement system4,15
- Complement activation is continuously occurring16-19
- Complement can be amplified by everyday occurrences such as bacterial and viral infections, allergies, and other trauma14,17,20,21
In aHUS, constant, uncontrolled complement activity leads to progressive and life-threatening complications4-6,14
While identification of a specific mutation can have prognostic implications, mutation identification overall has no impact on clinical outcome5,6
- 30%-50% of patients with aHUS have no currently identifiable genetic mutation23,24
- As of 2006, Caprioli reported 60 genetic mutations in CFH, MCP, and CFI6
- More than 120 mutations in these genes were reported by Noris in 20104
- Regardless of whether or not a mutation is identified, patients with aHUS have similarly devastating outcomes5,6
* Mutations consisted of membrane cofactor protein (MCP), complement factor H (CFH), and factor I (CFI). No mutation identified: n=81. Mutation identified: n=60.
† Mutations consisted of MCP, CFH, CFI, complement component 3 (C3), and thrombomodulin (THBD). No mutation identified: n=119. Mutation identified: n=116.
Regardless of whether or not a mutation is identified, patients with aHUS have similarly devastating outcomes5,6
Identification of genetic complement mutations is not required for aHUS diagnosis or management decisions5,25
4. Noris M, Mescia F, Remuzzi G. STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol. 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. Clin J Am Soc Nephrol. 2010;5:1844-1859. 6. Caprioli J, Noris M, Brioschi S, et al; for the International Registry of Recurrent 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. 9. Waters AM, Licht C. aHUS caused by complement dysregulation: new therapies on the horizon. Pediatr Nephrol. 2011;26:41-57. 13. Leban N, Abarrategui-Garrido C, Fariza-Requejo E, et al. Factor H and CFHR1 polymorphisms associated with atypical haemolytic uraemic syndrome (aHUS) are differently expressed in Tunisian and in Caucasian populations. Int J Immunogenet. 2012;39:110-113. 14. Hirt-Minkowski P, Dickenmann M, Schifferli JA. Atypical hemolytic uremic syndrome: update on the complement system and what is new. Nephron Clin Pract. 2010;114:c219-c235. 15. Loirat C, Noris M, Frémeaux-Bacchi V. Complement and the atypical hemolytic uremic syndrome in children. Pediatr Nephrol. 2008;23:1957-1972. 16. Loirat C, Saland J, Bitzan M. Management of hemolytic uremic syndrome. Presse Med. 2012;41:e115-e135. 17. Ricklin D, Hajishengallis G, Yang K, et al. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11:785-797. 18. Nester CM, Thomas CP. Atypical hemolytic uremic syndrome: what is it, how is it diagnosed, and how is it treated? Hematology Am Soc Hematol Educ Program. 2012;2012:617-625. 19. Barbour T, Johnson S, Cohney S, et al. Thrombotic microangiopathy and associated renal disorders. Nephrol Dial Transplant. 2012;27:2673-2685. 20. Wagner E, Frank MM. Therapeutic potential of complement modulation. Nat Rev Drug Discov. 2010;9:43-56. 21. Liszewski MK, Atkinson JP. Too much of a good thing at the site of tissue injury: the instructive example of the complement system predisposing to thrombotic microangiopathy. Hematology Am Soc Hematol Educ Program. 2011;2011:9-14. 22. Maga TK, Nishimura CJ, Weaver AE, et al. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat. 2010;31:E1445-E1460. 23. Kavanagh D, Goodship THJ. Atypical hemolytic uremic syndrome, genetic basis, and clinical manifestations. Hematology Am Soc Hematol Educ Program. 2011;2011:15-20. 24. Kavanagh D, Goodship THJ, Richards A. Atypical haemolytic uraemic syndrome. Br Med Bull. 2006;77-78:5-22. 25. Tsai H-M. Excessive activation of the complement system in atypical hemolytic uremic syndrome: is it ready for prime time? Kidney Int. 2010;77:267-269.