Natural History and Progression of Recurrent C3 Glomerulopathy and Primary Immune-Complex Membranoproliferative Glomerulonephritis in Kidney Transplantation

Background: 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.

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Journal
Clinical Journal of the American Society of Nephrology
Published
2026-06-29
DOI
https://doi.org/10.2215/cjn.0000001117
Primary Topic
Complement system in diseases
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article
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article

Natural History and Progression of Recurrent C3 Glomerulopathy and Primary Immune-Complex Membranoproliferative Glomerulonephritis in Kidney Transplantation

Joana Monteiro Dias, Sheila Cabello, Ana Huerta, Camilo Montero et al.
Clinical Journal of the American Society of Nephrology
Complement system in diseases
article

Natural History and Progression of Recurrent C3 Glomerulopathy and Primary Immune-Complex Membranoproliferative Glomerulonephritis in Kidney Transplantation

Joana Monteiro Dias, Sheila Cabello, Ana Huerta, Camilo Montero, Patricia Fox Concepción, Silvie Rajnochová-Bloudíčková, Raquél Rodado, Anna Buxeda, Elena Goicoechea de Jorge, Armando Coca, Annick Massart, Vítor Fernandes, Pilar Fraile Gómez, Rachel Hellemans, Constantino Fernández Rivera, Cristina Castro-Alonso, Luis Alberto Vigara, Sandra Habbig, Carme Facundo Molas, Fernando Caravaca‐Fontán, Iris Viejo-Boyano, Marius Miglinas, Manuel Praga, Edoardo Melilli, Leónidas Cruzado Vega, David Cucchiari, Candela Moliz, Loreto Fernandez Lorente, María Ramos Cebrián, Carlos Jiménez, Veline Martínez, Inmaculada Poveda, Amado Andrés, José María Mora‐Gutiérrez, Domingo Hernández, Pedro Fragoso, María José Pérez‐Sáez, Verónica López, L Curi, Natalia Menéndez García, Federico Yandián, Marios Papasotiriou, Nicolás Macías, Mariana Seija, Arzu Velioğlu, Joana Tavares, Paloma Leticia Martín-Moreno, Hernando Trujillo, İlay Berke, Irma Del Moral, Ayşe Serra Artan, Şafak Mirioğlu, Francesc Moreso, Miguel Ángel Pérez Valdivia, Ignacio Revuelta, Pilar Musalem, Lisa Eifler, Adriana Santos, Irina B. Torres, Andrés López Muñíz, Eduardo Gutiérrez, Núria Serra, María Molina, Manuel Macia, Lina León-Machado, Esther González Monte, Ana Isabel Diaz Mareque, Micaela Gerard, Ana Ávila, Emilio Rodrigo, Rita Guerra, Mayte Mora
article en

Abstract

Background: 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.

Clinical Journal of the American Society of Nephrology
Universidad Complutense de Madrid (ES), Universidad de Cantabria (ES), Innsbruck Medical University (AT), University of Antwerp (BE), Vilnius University (LT), Universidad de la República de Uruguay (UY), Hospital Universitario Insular de Gran Canaria (ES), Hospital Universitario de Canarias (ES), Hospital Universitario La Paz (ES), General University Hospital of Patras (GR), Bellvitge University Hospital (ES), Hospital General Universitario Gregorio Marañón (ES), Hospital de São João (PT), Hospital Universitari i Politècnic La Fe (ES), Research Institute Hospital 12 de Octubre (ES), Hospital Universitario Nuestra Señora de Candelaria (ES), Complejo Hospitalario Universitario de Santiago (ES), Hospital Infantil de México Federico Gómez (MX), Complejo Hospitalario de Navarra (ES), Complejo Hospitalario de Salamanca (ES), Hospital Carlos Van Buren (CL), Marqués de Valdecilla University Hospital (ES), Hospital Universitario 12 De Octubre (ES), Antwerp University Hospital (BE), Hospital Universitario Puerta de Hierro Majadahonda (ES), Hospital Regional Universitario de Málaga (ES), Administração Regional de Saúde de Lisboa e Vale do Tejo (PT), Instituto de Investigación Marqués de Valdecilla (ES), Hospital Clínic de Barcelona (ES), Hospital General Universitario de Elche (ES), Hospital Universitario Doctor Peset (ES), Hospital de Santo António (PT), Vall d'Hebron Hospital Universitari (ES), Institute of Clinical and Experimental Medicine (CZ), Hospital Juan Ramón Jiménez (ES), Hospital Del Mar (ES), Hospital Universitario Central de Asturias (ES), Clinica Universidad de Navarra (ES), Complexo Hospitalario Universitario A Coruña (ES), Puigvert Foundation (ES), Hospital Universitario Puerta del Mar (ES), Hospital Universitario Virgen de la Arrixaca (ES), Complejo Hospitalario Torrecárdenas (ES), Hospital Universitario Son Espases (ES), Hospital Universitario Virgen del Rocío (ES), Hospital Universitari Germans Trias i Pujol (ES), University Hospital Cologne (DE), Hospital de Clínicas (UY), Hospital Clínico Universitario de Valladolid (ES), Vilnius University Hospital Santariskiu Klinikos (LT), Fundación Universitaria Sanitas (CO), Instituto de Investigación Biomédica de Málaga (ES), Istanbul University (TR), Universidad de Montevideo (UY), Marmara University (TR), University of Coimbra (PT)
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Complement system in diseases
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