P1805UNEXPECTD COMPLEMENT GENES ABNORALITIES IN CHILDREN WITH SECONDARY HEMOLITIC UREMIC SYNDROME

Abstract

Abstract Background and Aims Secondary hemolytic-uremic syndrome (HUS) is currently defined in the absence of genetic defects in complement genes (primary or atypical HUS, aHUS) or Shiga-toxin producing E. Coli infection (STEC-HUS). However, the role of complement genes abnormalities in secondary HUS is still a matter of debate as results coming from studies performed in adults are controversial. Moreover, genetic defects of complement regulation have been recently described in children with STEC-HUS, thus challenging the current HUS classification. The identification of a role of complement genes abnormalities in these patients could have important clinical implications for diagnosis and treatment. In this study, we assessed the presence of complement genes abnormalities in children with secondary HUS. Method We describe a case series of pediatric patients diagnosed with secondary HUS. All patients were screened for the presence of ADAMTS13 auto-antibody and ADAMTS13 deficiency. We performed next-generation sequencing for a panel of complement genes reported in association with aHUS (CFH, CFI, MCP, C3, FB, and THBD). Copy number variations and hybrid genes assessment were included in the analysis. Results Four patients aged 1-4 years with a diagnosis of sporadic secondary HUS were included in the study. HUS was secondary to glomerulopathy, cobalamin deficiency, bone marrow transplantation, and pneumococcal pneumoniae. Two out of four patients showed hypocomplementaemia (both C3 and C4). Diarrhea was a common clinical feature in all patients at onset, and none of these patients showed neurologic involvement. Renal replacement therapy was required in two patients at onset. Only one patient did not recover kidney function, and subsequently underwent kidney transplantation. Next-generation sequencing showed genetic abnormalities in all the patients (Table 1). All but one genetic variants have already been described in association with atypical HUS. Interestingly, haplotypes in CHF and MCP were present in three patients, all of Caucasian ethnicity. Conclusion According to the current HUS classification, complement abnormalities are diagnostic of aHUS. However, results coming from pediatric cohorts of STEC-HUS patients already claimed a role for genetic background also outside the aHUS spectrum, suggesting that the current terminology lacks both specificity and suggestion of cause. In this case series, complement genes abnormalities were present in all patients. Whether confirmed in larger cohorts, these findings would support the role of genetic background even in secondary HUS, suggesting the need for a revision of the current HUS classification, in agreement with the pathogenic mechanisms, in order to tailor the optimal treatment.