Articles

Giulia Bassanese 1 , Joanna Sladowska-Kozlowska 1 , Enrique Morales Ruiz 2 , Marina Vivarelli 3 , Andrea Pasini 4 , Aude Servais 5 , Enrico Vidal 6 , Nele Kanzelmeyer 7 , Giulio Del Vecchio 8 , Rita Santarsiere 9 , Francesca Lugani 10 and Franz Schaefer 1

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1 Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, Heidelberg, Germany

2 Department of Nephrology, University Hospital of Madrid 12 de Octubre, Madrid, Spain

3 Laboratory of Nephrology and Clinical rial Center, Bambino Gesù Children’s Hospital ITCCS, Rome, Italy

4 Nephrology and Dialysis Unit, Department of Pediatrics, IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy

5 Nephrology and Transplantation Department, Centre de Référence des Maladies Rénales Héréditaires de l’Enfant et de l’Adulte, Necker Hospital, APHP, Université de Paris, Paris, France

6 Pediatric Nephrology Unit, Department of Women’s and Children’s Health, University of Padua, Padua, Italy

7 Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children’s Hospital, Hannover, Germany

8 University Center of Excellence on Nephrological, Rheumatological and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) including Nephrology and Dialysis Unit and Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley (North-West Italy), San Giovanni Bosco Hub Hospital, ASL Città di Torino and Department of Clinical and Biological Sciences of the University of Turin, Turin, Italy

9 Department of translational medical sciences, University of Campania ‘Luigi Vanvitelli’, Naples, Italy

10 Department of Pediatric Nephrology, IRCCS Istituto Giannina Gaslini, Genoa, Italy

 

Background and Aims: C3 glomerulopathy (C3G) and immune complex-mediated membranoproliferative glomerulonephritis (ic- MPGN) are chronic kidney disorders characterized by abnormal activation of the alternative complement pathway. The etiology of the conditions is heterogeneous and variably involves C3 activating auto-antibodies, alterations in complement regulating genes and activation of the terminal complement pathway. Classification by diagnostic biomarker panels has been proposed to improve outcome prediction. While currently available non-specific immunosuppressive and antiproteinuric therapies yield highly variable long-term disease outcomes, new treatments targeting individual components of the complement system are in development. These emerging novel therapeutic options increase the need for standardized, comprehensive diagnostic evaluation of C3G/ic-MPGN to empower rational, personalized treatment approaches.

 

The European Rare Kidney Disease Reference Network (ERKNet) and the CompCure Association for complement-mediated diseases have recently established a large prospective registry study following adults and children with C3G/ic-MPGN. The CompCure project aims to explore the association of diagnostic biomarkers with treatment responsiveness and disease outcomes. Here, we analyzed the completeness of available complement diagnostic features and the detection rate of abnormalities in the study cohort.

 

Method: A total of 236 patients were analyzed, including 157 with C3G (141 C3GN, 16 DDD) and 70 with ic-MPGN, registered across 36 European nephrology referral centers (30 pediatric, 11 adult). Disease onset was during childhood in 70% of the patients. 77% of patients were enrolled within 6 months of diagnosis. The diagnosis was established by kidney biopsy with immunofluorescence and electron microscopy in all cases.

 

Results: At time of diagnosis, global CH50 and AP50 complement tests were conducted in 26% and 15% of cases, respectively. While serum C3 was tested in 71% and C4 in 69% of patients, other complement proteins were rarely assessed: Factor H in 17%, C5 in 3%, and Properdin in 2%. The membrane attack complex (sC5b-9) was measured in 32%, and Bb in 4%. Among autoantibodies, C3Nef was tested in 33%, anti-FH in 31%, anti-FB in 9%, anti-C3b in 11%, and C5Nef in 5% of patients. Genetic testing was performed in 56% of C3GN, 75% of DDD, and 15% of ic-MPGN patients.

 

The assessment of core diagnostic features increased with time during the observation period:

 

Conclusion: The diagnostic evaluation of patients with C3G/ic-MPGN in European referral centers primarily relies on histopathological findings and serum C3 levels. Essential tests such as sC5b-9, C3Nef and other autoantibodies as well as complement gene screening are still performed in a minority of patients. Reasons for the incomplete diagnostic assessment may include the low number of specialized complement diagnostic laboratories in Europe, a lack of standardized diagnostic panels, high cost and long processing times. This gap in diagnostic practices hampers accurate disease classification and patient stratification for personalized treatment protocols. The CompCure cohort study will support participating sites to obtain standardized diagnostics in newly diagnosed patients with C3G/ic-MPGN.​​