Natural History and Progression of Recurrent C3 Glomerulopathy and Primary Immune-Complex Membranoproliferative Glomerulonephritis in Kidney Transplantation
José Enrique Ruiz-Cabello, Federico Yandian, Irina B Torres, Miguel Ángel Pérez Valdivia, Camilo Montero, Safak Mirioglu, Ayse Serra Artan, Ilay Berke, Silvie Rajnochová-Bloudíčková, Hernando Trujillo, Candela Moliz, María Molina, Iris Viejo, Sheila Cabello, Armando Coca, Patricia Fox Concepción, David Cucchiari, Paloma Leticia Martin-Moreno, Veline Martínez Calvache, Lina León-Machado, Anna Buxeda, Cristina Castro-Alonso, Andrés López Muñiz, Raquel Rodado, Natalia Menéndez García, Micaela Gerard, Marius Miglinas, Adriana Santos, Arzu Velioglu, Vítor Fernandes, Ana Isabel Díaz Mareque, Leónidas Cruzado-Vega, Núria Serra, Inmaculada Poveda, Irma del Moral, Mayte Mora, Joana Monteiro Dias, Nicolás Macías, Luis Alberto Vigara, Marios Papasotiriou, Lisa Eifler, Annick Massart, Ana Huerta, Rita Guerra, Loreto Fernández, Pilar Fraile, Pilar Musalem, Pedro Fragoso, Joana Tavares, Rachel Hellemans, Eduardo Gutiérrez, Esther González, Manuel Macía, José María Mora-Gutiérrez, Constantino Fernández Rivera, Ana Ávila, Verónica López, María Ramos-Cebrián, Edoardo Melilli, Domingo Hernández, Ignacio Revuelta, María José Pérez-Sáez, Emilio Rodrigo, Sandra Habbig, Lilián Curi, Mariana Seija, Carme Facundo, Carlos Jiménez, Francesc Moreso, Elena Goicoechea de Jorge, Amado Andrés, Manuel Praga, Fernando Caravaca-FontánBackground:
C3 glomerulopathy (C3G) and primary immune complex–mediated membranoproliferative glomerulonephritis (IC-MPGN) frequently recur after kidney transplantation and represent leading causes of graft loss. However, the natural history of recurrent disease and the prognostic value of longitudinal kidney biomarkers remain poorly defined.
Methods:
We conducted a multinational, retrospective cohort study of adults and children with biopsy-proven recurrent C3G or primary IC-MPGN in the kidney allograft (2001–2023). Patients were enrolled from 48 centers across 11 countries and required ≥4 serial measurements of estimated glomerular filtration rate (eGFR) and proteinuria after recurrence. Longitudinal trajectories of eGFR and proteinuria and their association with graft failure were evaluated using linear mixed-effects and Bayesian joint longitudinal–survival models. Complement genetic and autoantibody testing was performed in a subset of patients.
Results:
Of 332 eligible transplant recipients, 134 developed biopsy-proven recurrence (C3GN 60%, DDD 12%, IC-MPGN 28%). Median time to recurrence was 16 months, and 58% progressed to graft failure after a median follow-up of 62 months. Earlier recurrence, lower serum albumin, and higher histologic chronicity independently predicted failure. Joint models demonstrated that lower eGFR and higher proteinuria were dynamically associated with higher graft failure risk. Time-averaged proteinuria >1 g/day and eGFR lowering steeper than –5 mL/min/1.73 m 2 /year identified high-risk trajectories. Among 71 tested patients, 34% carried pathogenic complement variants and 23% had complement-directed autoantibodies; autoantibody-positive patients experienced earlier graft failure despite similar overall failure rates.
Conclusions:
Recurrent C3G and primary IC-MPGN after transplantation are associated with poor long-term outcomes, substantial histologic injury, and marked biological heterogeneity. Longitudinal eGFR and proteinuria provide powerful prognostic information, and clinically meaningful thresholds (>1 g/day time-averaged proteinuria; eGFR slope steeper than –5 mL/min/1.73 m 2 /year) refine risk stratification. Dynamic biomarkers may serve as surrogate endpoints, underscoring the need for prospective validation with emerging proximal complement therapies.