Complement factor H-related protein 1 deficiency and factor H antibodies in pediatric patients with atypical hemolytic uremic syndrome

Abstract

Background 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.

Figure 1.

Comparison between patients with atypical hemolytic uremic syndrome (aHUS) and healthy blood donors concerning presence of complement factor H (CFH) antibodies (by ELISA) and absence of CFHR1 gene (by PCR). CFHR1 PCR+/PCR− means homozygous CFHR1 deletion detected/not detected, respectively. The comparison of patients and controls shows a significantly greater percentage of CFHR1 homozygous deletions and CFH antibody within the patient group (P value was calculated using a chi-squared test). Ab, antibody; n/a, not available.

Figure 2.

Complement factor H (CFH) antibody (Ab) titer of five patients with atypical hemolytic uremic syndrome who were positive for CFH antibody and had homozygous CFHR1 deletion at acute phase of the disease and during remission. CFH antibody titer follow-up was recommended for all antibody-positive patients. However, because exact preanalytic treatment and shipment on dry ice are absolutely necessary, only some centers sent suitable samples for follow-up. Data for those patients are presented in this graph. Acute phase is defined as disease onset or disease recurrence. The area under the dashed line (<600 AU/ml) marks the area of suspected low recurrence risk according to the authors’ observations. Nevertheless, it is remarkable that patient I showed a CFH antibody titer of only 600 AU/ml at disease onset. In contrast to the other patients, serum for CFH antibody analysis in this patient was taken after plasmapheresis, suggesting a higher CFH antibody titer directly at disease onset. The cutoff level for CFH antibody positivity for ELISA in this study is 100 AU/ml.

Figure 3.

Prevalence of atypical hemolytic uremic syndrome (aHUS) and homozygous CFHR1 deletions. The calculation is based on 10⁷ individuals. The incidence of aHUS is estimated to be 1:10⁶ (41). In the current study, 32.2% (29/90) of patients with aHUS showed homozygous CFHR1 deletion compared with 2.5% (3/118) of healthy blood donors. On the basis of this frequency of homozygous CFHR1 deletions in the healthy population, an exclusive causative link appears to be highly unlikely.