Abstract Background and Aims Over the last decade, significant advancements have emerged in the field of rare kidney diseases, notably the introduction of C5 inhibitor therapy. The C5 inhibition has transformed the prognosis for atypical Hemolytic Uremic Syndrome (aHUS), offering improved clinical outcomes. However, despite these advancements, the utilization of C5 inhibitor therapy varies significantly, with disparities in treatment duration, reasons for discontinuation, and consideration of extending treatment to patients with infectious HUS (iHUS). This variability is further compounded by the considerable cost associated with C5 inhibitor treatment. Method This retrospective cohort study utilized data from the ERKNet Registry. The study cohort comprised 608 HUS patients enrolled in the ERKNet Registry between November 2018 and September 2023. The dataset encompassed patient demographics, disease and diagnostic records, medication profiles, dialysis or transplantation requirements, kidney function monitoring at the last visit, and clinical outcomes. Results Among 230 aHUS patients, 23 underwent kidney transplantation. 11 received C5 inhibitor therapy before kidney failure. The majority of these patients had genetic aHUS with various mutations (3 CFH, 2 CFI, and 1 CD46). The only death in the study was from this group of patients, unresponsive to C5 Inhibition. Out of 175 aHUS patients treated with Eculizumab, 23 (13%) transitioned to Ravulizumab. Among 104 patients who discontinued C5 inhibitors, 14 (14%) had to resume treatment, half of them with genetic aHUS, with 3 cases of CD46 mutations, 2 cases CFHR5 mutations, and one each involving mutations in CFI and C3. Only two patients required dialysis.. Among 371 iHUS patients, 82 (22%) received C5 Inhibitor treatment. Conclusion In the context of aHUS, we found that discontinuing C5 inhibitors is generally safe, with a slightly higher relapse rate in patients with complement gene variants, though most relapses were mild, requiring dialysis in only a few cases. Long-term follow-up revealed a return to normal kidney function following TMA relapses. Transitioning from Eculizumab to Ravulizumab exhibited promising outcomes, with no relapses or kidney failures in 23 patients. Our analysis of C5 inhibitor use in iHUS emphasized its association with more severe disease progression. While some studies question C5 inhibitors' acute-phase efficacy, others report remarkable improvements in patients unresponsive to other treatments. Overall, our findings underscore the safety of discontinuation practices, the potential benefits of Ravulizumab, and the ongoing need for further research on C5 inhibitor treatment in iHUS.
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