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Excessive complement activation plays a crucial role in the pathogenesis of atypical hemolytic uremic syndrome (aHUS). However, its involvement in Shiga Toxin-Producing Escherichia coli–Associated Hemolytic Uremic Syndrome (STEC-HUS) remains uncertain.
This study aimed to investigate the potential role of complement activation products and rare variants or disease risk polymorphisms in complement alternative pathway components in the pathogenesis of STEC-HUS.
We assessed complement activation products (C3a, C5a, and sC5b-9) and conducted next-generation sequencing of exonic regions of complement genes for Factor H (CFH), Factor I, Factor B, membrane cofactor protein (MCP), and C3 in 42 children with STEC, 12 children with STEC-positive diarrhea without HUS (STEC-D), and 72 healthy children (HC). We categorized STEC-HUS cases into "severe" (patients with more than 7 days of anuria, extrarenal manifestations, neurological sequelae, or those who died during the acute stage) and "non-severe."
There were no significant differences in the frequency of rare variants per gene or in the variant categorization among STEC-HUS, STEC-D, and HC groups. In severe STEC-HUS cases, the disease risk haplotype CFH-H3 was observed in 3 patients, and the risk haplotype MCPggaac was found in another 3 patients, all in homozygosity. A higher percentage of the protective haplotype CFH-H2, including the Val62Ile polymorphism, was present in STEC-D (36%) compared to STEC-HUS patients (25%).
Upon admission, C3a and sC5b-9 blood levels were significantly elevated in STEC-HUS patients compared to HC and STEC-D children. Severe STEC-HUS cases showed a significant increase in sC5b-9 levels compared to non-severe cases. There were no differences in C5a levels among the groups. A significant difference was observed in the ratio between FH-related protein1 and Factor H (FHR-1/FH) in STEC-HUS compared to HC, with the FHR-1/FH ratio being significantly higher in severe STEC-HUS cases.
A principal component analysis (PCA) was conducted to study the relationship between FH and complement activation products. The PCA, using FH as a comparison factor, revealed significant changes in both the direction and magnitude of the sC5b-9 vector related to STEC-D and HC. A Pearson matrix correlation analysis of all variables indicated a significant relationship between FH and sC5b-9. A separate PCA was also performed for severe and non-severe STEC-HUS patients, identifying leucocytes, C3a, sC5b-9, and FH as variables showing significant changes relative to the clinical status of both groups.
Our study demonstrated the activation of the alternative complement pathway, with a more pronounced activation in severe forms of STEC-HUS during the acute phase. Our results suggest a limited role of rare complement variants in STEC-HUS and that FHR-1 may provide valuable insights into the disease's pathogenesis for future studies.