Complement Factor H–Related Protein 1 Deficiency and Factor H Antibodies in Pediatric Patients with Atypical Hemolytic Uremic Syndrome

Abstract

SummaryBackground and objectives This study evaluated the relevance of complement factor H (CFH)-related protein (CFHR) 1 deficiency in pediatric patients with atypical hemolytic uremic syndrome (aHUS) by evaluating both the frequency of deletions in CFHR1 and the presence of complement factor H (CFH) antibodies.Design, setting, participants, & measurements A total of 116 patients (mainly from central Europe) and 118 healthy blood donors were included from 2001 to 2012. The presence of CFHR1 gene deletions was determined in 90 pediatric patients with aHUS and 118 controls by an easy, fast, and cheap PCR assay; 100 patients with aHUS and 42 controls were tested for CFH antibodies by ELISA. Questionnaires were administered to evaluate the clinical and laboratory data.Results Homozygous deletion in CFHR1 was detected in 32% of the patients with aHUS tested, compared with 2.5% of controls (P,0.001). CFH antibodies were present in 25% of the patients and none of the controls. CFH antibodies were detected in 82% of patients with homozygous CFHR1 gene deletion and in 6% of patients without. CFH antibody-positive patients with aHUS showed a significantly lower platelet nadir at disease onset and significantly less frequent involvement of the central nervous system than did antibody-negative patients. Antibody-positive patients also received plasma therapy more often.Conclusion Homozygous deletion in CFHR1 is strongly associated with occurrence of CFH antibodies in pediatric patients with aHUS. However, despite this apparent genetic disease predisposition, it cannot be considered an exclusive cause for aHUS. Initial presentation of Shiga toxin-negative HUS with severe thrombocytopenia and no central nervous system complications in pediatric patients is especially suspicious for CFH antibody aHUS.

Heterogeneity but individual constancy of epitopes, isotypes and avidity of factor H autoantibodies in atypical hemolytic uremic syndrome

“…The gene homology makes this genomic region prone to rearrangements that may result in hybrid genes and/or deletion of CFHR genes, which are associated with various diseases (reviewed in Jozsi et al 2015). In this context, about 90% of aHUS patients with FH autoantibodies are homozygous for the CFHR3-CFHR1 deletion (Abarrategui-Garrido et al 2009;Dragon-Durey et al 2009;Hofer et al 2013). Although this association is not completely understood, autoantibody generation/specificity is most likely related with the absence of FHR-1 in these patients.…”

Clinical guides for atypical hemolytic uremic syndrome in Japan

“…Loss-of-function and gain-of-function mutations both cause hyperactivation of the alternative complement pathway, which in turn induces aHUS by triggering endothelial damage and platelet aggregation. Anti-CFH autoantibodies have been detected in approximately 10 % of patients with aHUS [13]. These antibodies bind to the C-terminal domain of CFH and impair CFH-mediated cell surface protection by interfering with the interaction between CFH and its surface ligands.…”

A Case of CFH-Ab Hus Responsive to Plasmapheresis and with Sustained Remission after Initiation of Immunosuppressive Therapy Highlighting the Common Pit Falls of a Complicated Disease

“…CFH-Ab titers were determined using an ELISA as previously published [6]. Briefly, ELISA plates were coated with purified human CFH.…”