The role of the complement system in Shiga toxin-associated hemolytic uremic syndrome

Abstract

Background This research explores complement activation products involvement and risk and protective polymorphisms in the complement alternative pathway genes in Shiga toxin-associated hemolytic uremic syndrome (STEC-HUS) pathogenesis. Methods We analyzed the levels of complement activation products, C3a, C5a and soluble C5b-9 (sC5b-9) and plasma concentrations of Factor H (FH) and FH-related protein 1 (FHR-1) in 44 patients with STEC-HUS, 12 children with STEC- positive diarrhea (STEC-D), and 72 healthy controls (HC). STEC-HUS cases were classified as “severe” or “non-severe”. Genetic analysis was performed for complement genes (CFH, CFB, MCP, C3).Results No significant differences in the frequency of atypical HUS (aHUS) complement risk polymorphisms were found between groups. In severe STEC-HUS, the risk haplotypes CFH-H3 and MCPggaac were identified in three patients each, all in homozygosity. Patients with STEC-HUS had significantly elevated C3a, C5a and sC5b-9 levels at admission com- pared to HC and STEC-D, with higher sC5b-9 levels in severe cases. Increased ratio between FHR-1 and FH (FHR-1/FH) was demonstrated in STEC-HUS vs. HC, with significantly higher FHR-1/FH ratio in severe STEC-HUS patients. Principal component analysis revealed significant changes in sC5b-9 direction and magnitude in STEC-HUS. Pearson correlation showed a significant relationship between FH and sC5b-9. Logistic regression indicated sC5b-9, leukocytosis, creatinine, and anuria duration as independent factors for severe STEC- HUS.Conclusions This study highlights the significant activation of the alternative complement pathway in STEC-HUS, particu- larly sC5b-9 in severe cases, and suggests a limited contribution of complement risk polymorphisms in STEC-HUS. FHR-1 may represent a promising target for future investigations related to STEC-HUS pathogenesis.