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. 2025 Mar 27:82:103159.
doi: 10.1016/j.eclinm.2025.103159. eCollection 2025 Apr.

Real-world use of complement inhibitors for haemolytic uraemic syndrome: an analysis of the European Rare Kidney Disease Registry cohort

Aleksandra Vujović  1   2 , Anne-Laure Sellier-Leclerc  3 , Maria Cristina Mancuso  4 , Olivia Boyer  5 , Atif Awan  6 , Antonio Gargiulo  7 , Sebastian Loos  8 , Marc Fila  9 , Augustina Jankauskiene  10 , Gema Ariceta  11 , Nele Kanzelmeyer  12 , Enrico Vidal  13 , Maria Van Dyck  14 , Tanja Kersnik Levart  1 , Naděžda Šimánková  15 , Stephane Decramer  16   17   18 , Jonas Hofstetter  19 , Marina Vivarelli  7 , Savino Sciascia  20 , Nicole C A J van de Kar  21 , Franz Schaefer  19 ; ERKNet TMA Working Group
Collaborators, Affiliations

Real-world use of complement inhibitors for haemolytic uraemic syndrome: an analysis of the European Rare Kidney Disease Registry cohort

Aleksandra Vujović et al. EClinicalMedicine. .

Abstract

Background: Although terminal complement inhibitors transformed the prognosis of atypical haemolytic uraemic syndrome (aHUS) from dismal to favourable, treatment approaches vary due to the intermittent disease nature and high costs. Occasionally, complement inhibition is applied in infectious (i)HUS. We aimed to examine real-world C5 inhibitor use and its impact on patient outcomes.

Methods: This retrospective cohort study used longitudinal data from the European Rare Kidney Disease Registry, collected from 76 nephrology centres across 24 European countries between January 1, 2019 and January 31, 2024. Eligible patients had aHUS or iHUS with onset after January 1, 2011, and/or documented C5 inhibitor use. Exclusions included complement-unrelated HUS, post-transplant HUS, and prophylactic C5 inhibitor use around kidney transplantation. Data, derived from medical records and focused queries, were used to assess C5 inhibitor duration, via time-to-event analysis, and kidney function based on annual creatinine levels.

Findings: A total of 238 aHUS and 472 patients with iHUS were included in the analysis. C5 inhibition was applied in 76.5% of aHUS and 18.4% of iHUS, with major utilisation differences between countries (p < 0.0001) and less common use in female patients with aHUS (p = 0.0022). Median (interquartile range) treatment duration was 16.1 (3.6-41.2) months in aHUS and 9 (7-32) days in iHUS. After five years, 56% of genetic, 28% of anti-complement factor H (anti-CFH) antibody-mediated, and 23% of aHUS cases with no identified cause remained on treatment. The long-term (>7 years) risk of treatment resumption was 35% in genetic, 15% in aHUS of no identified cause, and 0% in anti-CFH antibody-mediated aHUS. Post-withdrawal aHUS relapses were mostly mild and did not lead to permanent kidney function impairment, ultimately leading to long-term treatment withdrawal in 92.5% of discontinued cases.

Interpretation: Currently, C5 inhibitors are administered in three-quarters of newly diagnosed patients with aHUS in Europe, with varied utilisation and discontinuation practices. Treatment withdrawal is common and safe, although relapses may occur, particularly in genetic aHUS. However, baseline disease severity, selective use in expert centres, and indication bias affect outcome comparability. Findings must be considered in the context of patient-specific factors and disease severity at the time of treatment decisions.

Funding: This research was supported by the European Reference Network for Rare Kidney Diseases, funded by the European Union within the framework of the "EU4Health Programme 2021-2027".

Keywords: Complement inhibitor; European Rare Kidney Disease Registry; Haemolytic uraemic syndrome; Post-withdrawal relapse; Treatment discontinuation.

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Conflict of interest statement

All authors declare the following potential conflicts of interest related to the content of this manuscript: MCM received speaker honoraria and a travel grant from Alexion. OB received speaker honoraria from Alexion and Samsung. AA served on the Data Monitoring Committee for the UK trial on C5 inhibitor discontinuation. MF received speaker honoraria, payment for expert testimony, consultancy fees, and a travel grant from Alexion. GA received speaker honoraria and travel grants from Alexion (AstraZeneca Rare Diseases) and served on its Board. JH works as a statistician at ERKNet, which received payments from Vertex, Novartis, and Sobi for research collaborations. JH performed statistical analyses and created project reports on behalf of ERKNet: “Analysis of the ERKReg database for ADPKD & AMKD studies” for Vertex, “Disease characteristics and treatment patterns of C3G and IC-MPGN in Europe: a multicentre retrospective analysis using the ERKReg database” for Novartis, and “A C3G and Primary IC-MPGN Retrospective Observational Study - Fit-For-Purpose Summary Report” for Sobi. MV received consultancy fees from Novartis, BioCryst, Roche, Apellis, speaker honoraria from Roche, Novartis, Alexion, Vifor, and Travere, and a grant from the Italian Ministry of Health to her institution. NCAJVDK received grants from Apellis and Novartis as principal or sub-investigator for international trials on pegcetacoplan and iptacopan for C3G treatment, consulting fees from Samsung, Alexion, and Novartis, speaker fees from Novartis and Sobi, travel grants from Samsung and Sobi, and served on a board for Roche, with all payments made to her institution. FS received consulting fees from Samsung Bioepis for participation in Scientific Advisory Board meetings, with payment made to him, and from Alexion for consulting on paediatric trial programs in potential new indications for C5 inhibitors while participating in the sAlexion Global aHUS Registry Steering Committee, with payments made to his institution. The remaining authors declare no conflicts of interest. No other relevant affiliations or financial involvements exist beyond those disclosed.

Figures

Fig. 1
Fig. 1
Disposition of C5 inhibitor treatment in haemolytic uraemic syndrome (HUS) cohort. This figure shows the distribution of patients based on their treatment status. Orange represents permanent treatment discontinuation, and green indicates sustained treatment. Abbreviations: HUS—haemolytic uraemic syndrome; iHUS—infectious haemolytic uraemic syndrome; aHUS—atypical haemolytic uraemic syndrome.
Fig. 2
Fig. 2
Duration of C5 inhibitor treatment by haemolytic uraemic syndrome (HUS) aetiology. This figure illustrates the duration of C5 inhibitor treatment across different HUS aetiologies. Green shows genetic aHUS, red indicates anti-CFH antibody-mediated aHUS, blue represents cases with no identified cause, and pink represents iHUS cases. Abbreviations: %—percentage; aHUS—atypical haemolytic uraemic syndrome; anti-CFH ab—anti-complement factor H antibody-mediated aHUS; iHUS—infectious haemolytic uraemic syndrome. Data availability for the duration of C5 inhibitor treatment: genetic aHUS 69/69, anti-CFH antibody-mediated aHUS 39/40, aHUS with no identified cause 73/73, and iHUS 87/87.
Fig. 3
Fig. 3
Duration of C5 inhibitor treatment in patients with genetic atypical haemolytic uraemic syndrome (aHUS) by affected gene. This figure depicts the duration of C5 inhibitor treatment in patients with genetic aHUS categorised by their affected genes. Red indicates CFH mutations, blue CFI mutations, green C3 mutations, and pink CD46 mutations. Abbreviations: %—percentage; CFH—complement factor H; CFI—complement factor I; C3—complement component 3; CD46—CD46 molecule. Data availability for the duration of C5 inhibitor treatment in genetic aHUS: CFH 22/23, CFI 7/7, C3 10/10, and CD46 21/21.
Fig. 4
Fig. 4
Utilisation of C5 inhibitors in patients with atypical haemolytic uraemic syndrome (aHUS) by country of residence. This figure illustrates the variation in C5 inhibitor use among patients with aHUS across different countries. Blue bars show the fraction of patients ever treated, and green bars the likelihood of remaining on treatment 12 months after initiation (based on Kaplan–Meier analysis). Czechia (n = 9), Poland (n = 9), Belgium (n = 6), Spain (n = 14), Germany (n = 34), France (n = 44), Romania (n = 8), Italy (n = 33), The Netherlands (n = 5), Lithuania (n = 4), and Ireland (n = 5). Abbreviations: %—percentage; aHUS—atypical haemolytic uraemic syndrome; pts—patients, mo—months.
Fig. 5
Fig. 5
Time to treatment resumption following C5 inhibitor withdrawal in patients with atypical haemolytic uraemic syndrome (aHUS). This figure displays the time to treatment resumption after C5 inhibitor withdrawal, categorised by aHUS aetiology. Green indicates genetic aHUS, blue cases with no identified cause, and red anti-CFH antibody-mediated aHUS cases. Abbreviations: %—percentage; aHUS—atypical haemolytic uraemic syndrome; anti-CFH ab—anti-complement factor H antibody-mediated aHUS. Data availability: Time to treatment resumption data available for 107/107 aHUS patients.
Fig. 6
Fig. 6
Kidney function outcomes by chronic kidney disease (CKD) stage in patients with atypical haemolytic uraemic syndrome (aHUS) followed for more than 3 months. Outcomes are stratified by aHUS type and C5 inhibitor treatment modality (sustained, discontinued, or never treated). This figure represents kidney function outcomes stratified by CKD stage, aHUS type, and C5 inhibitor treatment modality. Blue represents CKD stage 1, green stage 2, yellow stage 3, orange stage 4, and red stage 5. Abbreviations: Nr—number; %—percentage; CKD—chronic kidney disease; aHUS—atypical haemolytic uraemic syndrome; anti-CFH antibody—anti-complement factor H antibody-mediated aHUS. Data availability: 208/208 aHUS patients followed for more than 3 months.
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