Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype

Marina Noris, Jessica Caprioli, Elena Bresin, Chiara Mossali, Gaia Pianetti, Sara Gamba, Erica Daina, Chiara Fenili, Federica Castelletti, Annalisa Sorosina, Rossella Piras, Roberta Donadelli, Ramona Maranta, Irene Van Der Meer, Edward M. Conway, Peter F. Zipfel, Timothy H. Goodship, Giuseppe Remuzzi

Research output: Contribution to journalArticle

Abstract

Background and objectives: Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Most childhood cases are caused by Shiga toxin-producing bacteria. The other form, atypical HUS (aHUS), accounts for 10% of cases and has a poor prognosis. Genetic complement abnormalities have been found in aHUS. Design, setting, participants, and measurements: We screened 273 consecutive patients with aHUS for complement abnormalities and studied their role in predicting clinical phenotype and response to treatment. We compared mutation frequencies and localization and clinical outcome in familial (82) and sporadic (191) cases. Results: In >70% of sporadic and familial cases, gene mutations, disease-associated factor H (CFH) polymorphisms, or anti-CFH autoantibodies were found. Either mutations or CFH polymorphisms were also found in the majority of patients with secondary aHUS, suggesting a genetic predisposition. Familial cases showed a higher prevalence of mutations in SCR20 of CFH and more severe disease than sporadic cases. Patients with CFH or THBD (thrombomodulin) mutations had the earliest onset and highest mortality. Membrane-cofactor protein (MCP) mutations were associated with the best prognosis. Plasma therapy induced remission in 55 to 80% of episodes in patients with CFH, C3, or THBD mutations or autoantibodies, whereas patients with CFI (factor I) mutations were poor responders. aHUS recurred frequently after kidney transplantation except for patients with MCP mutations. Conclusions: Results underline the need of genetic screening for all susceptibility factors as part of clinical management of aHUS and for identification of patients who could safely benefit from kidney transplant.

Original languageEnglish
Pages (from-to)1844-1859
Number of pages16
JournalClinical Journal of the American Society of Nephrology
Volume5
Issue number10
DOIs
Publication statusPublished - Oct 1 2010

ASJC Scopus subject areas

  • Nephrology
  • Transplantation
  • Epidemiology
  • Critical Care and Intensive Care Medicine

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    Noris, M., Caprioli, J., Bresin, E., Mossali, C., Pianetti, G., Gamba, S., Daina, E., Fenili, C., Castelletti, F., Sorosina, A., Piras, R., Donadelli, R., Maranta, R., Van Der Meer, I., Conway, E. M., Zipfel, P. F., Goodship, T. H., & Remuzzi, G. (2010). Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clinical Journal of the American Society of Nephrology, 5(10), 1844-1859. https://doi.org/10.2215/CJN.02210310