Bocanegra Victoria, Luna Mariana, Costantino Valeria V, Lorenzo Andrea F Gil, Marino Raul, Miatello Roberto, Cacciamani Valeria, Benardon M Eugenia, Godoy Clara Pott, Pinto Sheila, de Córdoba Santiago Rodríguez, Vallés Patricia G
Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET, Buenos Aires, Argentina.
Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina.
Pediatr Nephrol. 2025 May;40(5):1711-1722. doi: 10.1007/s00467-024-06629-6. Epub 2025 Jan 10.
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.
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).
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 compared 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.
This study highlights the significant activation of the alternative complement pathway in STEC-HUS, particularly 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.
本研究探讨补体激活产物的参与情况以及志贺毒素相关溶血尿毒综合征（STEC-HUS）发病机制中补体替代途径基因的风险和保护性多态性。
我们分析了44例STEC-HUS患者、12例STEC阳性腹泻（STEC-D）儿童和72例健康对照（HC）的补体激活产物C3a、C5a和可溶性C5b-9（sC5b-9）水平以及血浆中因子H（FH）和FH相关蛋白1（FHR-1）的浓度。STEC-HUS病例分为“重症”或“非重症”。对补体基因（CFH、CFB、MCP、C3）进行了基因分析。
各组间非典型溶血尿毒综合征（aHUS）补体风险多态性的频率无显著差异。在重症STEC-HUS中，CFH-H3和MCPggaac风险单倍型在3例患者中被鉴定出，均为纯合子。与HC和STEC-D相比，STEC-HUS患者入院时C3a、C5a和sC5b-9水平显著升高，重症病例中sC5b-9水平更高。与HC相比，STEC-HUS患者中FHR-1与FH的比值（FHR-1/FH）升高，重症STEC-HUS患者的FHR-1/FH比值显著更高。主成分分析显示STEC-HUS中sC5b-9的方向和幅度有显著变化。Pearson相关性分析显示FH与sC5b-9之间存在显著关系。逻辑回归表明sC5b-9、白细胞增多、肌酐和无尿持续时间是重症STEC-HUS的独立因素。
本研究强调了STEC-HUS中补体替代途径的显著激活，尤其是重症病例中的sC5b-9，并表明补体风险多态性在STEC-HUS中的作用有限。FHR-1可能是未来与STEC-HUS发病机制相关研究的一个有前景的靶点。
