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

KEY POINTS: In 134 kidney transplant recipients with recurrent C3 glomerulopathy/immune complex-mediated membranoproliferative GN, 58% lost the graft, confirming the poor long-term prognosis. Time-averaged proteinuria >1 g/d and eGFR decline >5 ml/min per 1.73 m 2 per year predicted higher graft failure risk. Complement profiling showed heterogeneity; autoantibody-positive patients lost grafts earlier, supporting personalized care. BACKGROUND: C3 glomerulopathy (C3G) and primary immune complex-mediated membranoproliferative GN (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 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%, dense deposit disease 12%, IC-MPGN 28%). The 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/d and eGFR lowering steeper than -5 ml/min per 1.73 m 2 per 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 biologic heterogeneity. Longitudinal eGFR and proteinuria provide powerful prognostic information and clinically meaningful thresholds (>1 g/d time-averaged proteinuria; eGFR slope steeper than -5 ml/min per 1.73 m 2 per year) refine risk stratification. Dynamic biomarkers may serve as surrogate end points, underscoring the need for prospective validation with emerging proximal complement therapies.