Hemolytic Uremic Syndrome, Genetic

Living reference work entry


The nomenclature of atypical hemolytic uremic syndrome (aHUS) has undergone an evolution as rapid as the scientific understanding of the field during the last decade. Identification of many underlying genetic causes has increased understanding of the major mechanisms of disease. These defects principally, but not exclusively, involve the alternative pathway of complement. Important differences among the specific defects have impact on disease management, and clinical genetics plays a key role in that process. Untreated, aHUS frequently leads to end stage renal disease or death. Fortunately, understanding the major disease mechanisms has allowed development of effective treatment options.


Hemolytic uremic syndrome Complement Alternative pathway Hemolytic anemia Thrombocytopenia Thrombotic microangiopathy Factor H Eculizmuab Plasmapheresis Plasma exchange 


  1. Azukaitis K, Simkova E, Majid MA, Galiano M, Benz K, Amann K et al (2017) The phenotypic spectrum of nephropathies associated with mutations in diacylglycerol kinase epsilon. J Am Soc Nephrol 28(10):3066–3075CrossRefGoogle Scholar
  2. Beck BB, van Spronsen F, Diepstra A, Berger RM, Komhoff M (2017) Renal thrombotic microangiopathy in patients with cblC defect: review of an under-recognized entity. Pediatr Nephrol 32:733–741. 2016 Jun 11CrossRefGoogle Scholar
  3. Benamu E, Montoya JG (2016) Infections associated with the use of eculizumab: recommendations for prevention and prophylaxis. Curr Opin Infect Dis 29(4): 319–329CrossRefGoogle Scholar
  4. Berger BE (2016) The alternative pathway of complement and the evolving clinical-pathophysiological Spectrum of atypical hemolytic uremic syndrome. Am J Med Sci 352(2):177–190CrossRefGoogle Scholar
  5. Bresin E, Rurali E, Caprioli J, Sanchez-Corral P, Fremeaux-Bacchi V, Rodriguez de Cordoba S et al (2013) Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype. J Am Soc Nephrol 24(3):475–486CrossRefGoogle Scholar
  6. Brown JH, Tellez J, Wilson V, Mackie IJ, Scully M, Tredger MM et al (2012) Postpartum aHUS secondary to a genetic abnormality in factor H acquired through liver transplantation. Am J Transplant 12(6): 1632–1636CrossRefGoogle Scholar
  7. Coppo R, Bonaudo R, Peruzzi RL, Amore A, Brunati A, Romagnoli R et al (2016) Liver transplantation for aHUS: still needed in the eculizumab era? Pediatr Nephrol 31(5):759–768CrossRefGoogle Scholar
  8. Durey MA, Sinha A, Togarsimalemath SK, Bagga A (2016) Anti-complement-factor H-associated glomerulopathies. Nat Rev Nephrol 12(9):563–578CrossRefGoogle Scholar
  9. Feng S, Eyler SJ, Zhang Y, Maga T, Nester CM, Kroll MH et al (2013) Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome. Blood 122(8):1487–1493CrossRefGoogle Scholar
  10. Fremeaux-Bacchi V, Arzouk N, Ferlicot S, Charpentier B, Snanoudj R, Durrbach A (2007) Recurrence of HUS due to CD46/MCP mutation after renal transplantation: a role for endothelial microchimerism. Am J Transplant 7(8):2047–2051CrossRefGoogle Scholar
  11. Fremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaime F, Dragon-Durey MA, Ngo S et al (2013) Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol 8(4):554–562CrossRefGoogle Scholar
  12. George JN, Nester CM (2014) Syndromes of thrombotic microangiopathy. N Engl J Med 371(7):654–666CrossRefGoogle Scholar
  13. Goodship TH, Cook HT, Fakhouri F, Fervenza FC, Fremeaux-Bacchi V, Kavanagh D et al (2017) Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney disease: improving global outcomes” (KDIGO) controversies conference. Kidney Int 91:539–551. 2016 Dec 15CrossRefGoogle Scholar
  14. Greenbaum L (2016) The physician’s guide to atypical hemolytic uremic syndrome (aHUS). In: (NORD) NOfRD, editor. http://www.nordphysicianguidesorg/wp-content/uploads/2015/12/NORD_Physician%E2%80%99s-Guide-to-AHUS.pdf
  15. Gurjar BS, Sriharsha TM, Bhasym A, Prabhu S, Puraswani M, Khandelwal P, et al (2018) Characterization of genetic predisposition and autoantibody profile in atypical hemolytic uremic syndrome. Immunology. [Epub ahead of print]. PMID:29485195
  16. Hirt-Minkowski P, Dickenmann M, Schifferli JA (2010) Atypical hemolytic uremic syndrome: update on the complement system and what is new. Nephron Clin Pract 114(4):c219–c235CrossRefGoogle Scholar
  17. Kavanagh D, Goodship T (2010) Genetics and complement in atypical HUS. Pediatr Nephrol 25(12): 2431–2442CrossRefGoogle Scholar
  18. Kavanagh D, Goodship TH, Richards A (2013) Atypical hemolytic uremic syndrome. Semin Nephrol 33(6): 508–530CrossRefGoogle Scholar
  19. Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C et al (2013) Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 368(23):2169–2181CrossRefGoogle Scholar
  20. Lemaire M, Fremeaux-Bacchi V, Schaefer F, Choi M, Tang WH, Le Quintrec M et al (2013) Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet 45(5):531–536CrossRefGoogle Scholar
  21. Loirat C, Fremeaux-Bacchi V (2011) Atypical hemolytic uremic syndrome. Orphanet J Rare Dis 6:60CrossRefGoogle Scholar
  22. Loirat C, Fremeaux-Bacchi V (2014) Anti-factor H autoantibody-associated hemolytic uremic syndrome: the earlier diagnosed and treated, the better. Kidney Int 85(5):1019–1022CrossRefGoogle Scholar
  23. Loirat C, Saland J, Bitzan M (2012) Management of hemolytic uremic syndrome. Presse Med 41(3 Pt 2):e115–e135CrossRefGoogle Scholar
  24. Loirat C, Fakhouri F, Ariceta G, Besbas N, Bitzan M, Bjerre A et al (2016) An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol 31(1): 15–39CrossRefGoogle Scholar
  25. Malina M, Roumenina LT, Seeman T, Le Quintrec M, Dragon-Durey MA, Schaefer F et al (2012) Genetics of hemolytic uremic syndromes. Presse Med 41(3 Pt 2):e105–e114CrossRefGoogle Scholar
  26. Murphy K (2008) Janeway’s immunobiology, 7th edn. Garland Science, New YorkGoogle Scholar
  27. Nester CM, Barbour T, de Cordoba SR, Dragon-Durey MA, Fremeaux-Bacchi V, Goodship TH et al (2015) Atypical aHUS: state of the art. Mol Immunol 67(1): 31–42CrossRefGoogle Scholar
  28. Nishimura J, Yamamoto M, Hayashi S, Ohyashiki K, Ando K, Brodsky AL et al (2014) Genetic variants in C5 and poor response to eculizumab. N Engl J Med 370(7):632–639CrossRefGoogle Scholar
  29. Noris M, Remuzzi G (2013) Overview of complement activation and regulation. Semin Nephrol 33(6): 479–492CrossRefGoogle Scholar
  30. Osborne AJ, Breno M, Borsa NG, Bu F, Fremeaux-Bacchi V, Gale DP et al (2018) Statistical validation of rare complement variants provides insights into the molecular basis of atypical hemolytic uremic syndrome and C3 glomerulopathy. J Immunol 200:2464–2478. 2018 Mar 2CrossRefGoogle Scholar
  31. Picard C, Burtey S, Bornet C, Curti C, Montana M, Vanelle P (2015) Pathophysiology and treatment of typical and atypical hemolytic uremic syndrome. Pathol Biol 63(3):136–143CrossRefGoogle Scholar
  32. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–424CrossRefGoogle Scholar
  33. Saland J (2014) Liver-kidney transplantation to cure atypical HUS: still an option post-eculizumab? Pediatr Nephrol 29(3):329–332CrossRefGoogle Scholar
  34. Saland JM, Ruggenenti P, Remuzzi G, Consensus Study G (2009) Liver-kidney transplantation to cure atypical hemolytic uremic syndrome. J Am Soc Nephrol 20(5):940–949CrossRefGoogle Scholar
  35. Saland J, Satlin L, Zalsos-Johnson J, Cremers S, Ginsberg H (2016) Impaired postprandial lipemic response in chronic kidney disease. Kidney Int 90:172–180. in pressCrossRefGoogle Scholar
  36. Vieira-Martins P, El Sissy C, Bordereau P, Gruber A, Rosain J, Fremeaux-Bacchi V (2016) Defining the genetics of thrombotic microangiopathies. Transfus Apher Sci 54(2):212–219CrossRefGoogle Scholar
  37. Yuksel S, Evrengul H, Ozcakar ZB, Becerir T, Yalcin N, Korkmaz E et al (2016) First-line, early and long-term eculizumab therapy in atypical hemolytic uremic syndrome: a case series in pediatric patients. Paediatr Drugs 18(6):413–420CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PediatricsThe Kravis Children’s Hospital at Mount Sinai, The Icahn School of Medicine at Mount SinaiNew YorkUSA
  2. 2.Department of PediatricsCohen Children’s Hospital, Donald and Barbara Zucker School of Medicine at Hofstra/NorthwellHempsteadUSA

Personalised recommendations