#1196 C3G and ic-MPGN across the life span: findings from the European Rare Kidney Disease Registry
Authors: Schaefer Franz , Hofstetter Jonas , Ruiz Enrique Morales , Antonucci Luca , Conlon Peter J , Francesca Becherucci , Servais Aude , Kanzelmeyer Nele , Beltran Victor Perez , Imeraj Amantia , Mastrangelo Antonio , Roccatello Dario 
Published: May 2024

Abstract

Background and Aims
C3 glomerulopathy (C3G) and immune complex-membranoproliferative glomerulonephritis (ic-MPGN) are two complement-mediated rare kidney disorders affecting both adults and children for which innovative therapies are under development. Due to the low prevalence and difficult diagnosis of the diseases, demographic and kidney outcome data are scarce. To obtain such information, we interrogated the European Rare Kidney Disease Registry (ERKReg), a Pan-European database of patients with rare kidney diseases treated at specialized adult and pediatric nephrology centers.

Method
Data on all patients diagnosed with C3G or ic-MPGN were extracted from the ERKReg database, to which more than 22, 000 incident and prevalent patients with rare kidney diseases were enrolled between October 2018 and December 2023. After exclusion of 32 patients with reported disease onset prior to 1998 to ensure compliance with contemporaneous diagnostic and treatment standards, 225 C3G and 173 ic-MPGN patients from 32 pediatric and 12 adult nephrology units in 16 European countries were available for analysis. Among these, 20.4% of C3G and 10.4% of ic-MPGN were incident patients who were enrolled either within 3 months of diagnosis or had diagnostic confirmation of suspected disease during prospective follow-up in ERKReg. Kaplan Meier actuarial survival analysis was performed to calculate time to kidney failure. Survival rates are given as median estimates and 95% confidence intervals. The impact of disease type and age at disease onset on kidney survival was assessed by Cox regression analysis.

Results
Overall, 80.9% of C3G and 33.5% of ic-MPGN patients had disease onset in childhood; the median (IQR) age at diagnosis was 12.4 (8.4-16.2) years for C3G and 38.9 (12.1-57.6) years for ic-MPGN. Genetic variants in CFH, CFHR1/3/5 and CFB were identified in 13 C3G (10.7% of tested) and 4 (14.8% of tested) ic-MPGN patients, and CFH autoantibodies in another 7 (17% of tested) C3G patients.
Among the incident patients, 71.7% presented in CKD1 and 6.5% in CKD4/5 for C3G, as compared to 27.8% CKD1 and 27.7% CKD4/5 for ic-MPGN. Nephrotic-range proteinuria was present in 34% of incident C3G and 44% of ic-MPGN patients respectively.
At last observation, 7.8% of childhood-onset and 17.1% of adult-onset C3G patients were on kidney replacement therapy (KRT) (thereof 71% and 86% with functioning transplant, respectively). For ic-MPGN at last observation, 14.6% of childhood-onset and 38.9% of adult-onset received KRT (thereof 62.5% and 69.0% with functioning graft, respectively).
Kidney survival rates are given in the table below:
The risk of progression to kidney failure within the observation period was approximately 60% higher in ic-MPGN vs. C3G (HR: 1.6; CI 95%: 0.9-2.8; p = 0.06) and was twice as high in patients with adult vs. pediatric disease onset (HR: 2.0; CI 95%: 1.2-3.3; P = .01).

Conclusion
C3G tends to manifest at earlier age than ic-MPGN. Altered complement regulation can be identified in subsets of patients with both disorders. Functional kidney impairment at first disease manifestation is more common and progression to kidney failure occurs more rapidly with ic-MPGN vs. C3G. Disease onset at adult age is associated with a more rapid disease progression compared to childhood-onset disease.