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


METHODS
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.
Noris
Marina
M
Mario Negri Institute for Pharmacological Research, Clinical Research Center for Rare Diseases, Aldo e Cele Daccò, Via Camozzi, 3-24020 Ranica (BG), Italy. marina.noris@marionegri.it.
Caprioli
Jessica
J
Bresin
Elena
E
Mossali
Chiara
C
Pianetti
Gaia
G
Gamba
Sara
S
Daina
Erica
E
Fenili
Chiara
C
Castelletti
Federica
F
Sorosina
Annalisa
A
Piras
Rossella
R
Donadelli
Roberta
R
Maranta
Ramona
R
van der Meer
Irene
I
Conway
Edward M
EM
Zipfel
Peter F
PF
Goodship
Timothy H
TH
Remuzzi
Giuseppe
G
D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D001323:Autoantibodies / Q000097:blood; D016009:Chi-Square Distribution; D003176:Complement C3 / Q000235:genetics; D017242:Complement Factor H / Q000235:genetics; D003165:Complement System Proteins / Q000235:genetics* / Q000276:immunology; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000628:therapy; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D016030:Kidney Transplantation; D008297:Male; D051916:Membrane Cofactor Protein / Q000235:genetics; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D012008:Recurrence; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D018180:Thrombomodulin / Q000235:genetics; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
D001323:Autoantibodies; C038245:C3 protein, human; C497857:CD46 protein, human; C493495:CFH protein, human; D003176:Complement C3; D051916:Membrane Cofactor Protein; C546931:THBD protein, human; D018180:Thrombomodulin; D017242:Complement Factor H; D003165:Complement System Proteins