Recurrence of C3 Glomerulopathy and Immune Complex–Mediated Membranoproliferative Glomerulonephritis After Kidney Transplantation - Challenges and Opportunities

Sep 29, 2026

Uploaded by Levi

Recurrence of C3 glomerulopathy (C3G) and primary immune complex–mediated membranoproliferative glomerulonephritis (IC-MPGN) drives major kidney allograft dysfunction after transplantation, with recurrence rates often exceeding 60% and linked to progression to graft failure. Pathogenesis spans genetic susceptibility, acquired complement dysregulation, and transplant-related triggers, yet validated recurrence predictors are lacking. Protocol biopsies can enable early detection but histologic recognition is difficult. The review summarizes clinical spectrum, diagnostic and therapeutic challenges, and emerging complement-targeted strategies, including eculizumab and proximal inhibitors such as iptacopan and pegcetacoplan, while noting uncertainty on timing, prophylaxis, and long-term safety.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Recurrence Rates and Natural History

Early Detection and Histologic Recognition

Risk Stratification and Pretransplant Evaluation

Treatment Limitations of Conventional Approaches

Emerging Complement-Targeted Therapies and Safety Considerations

REVIEW Recurrence of C3 Glomerulopathy and Immune Complex–Mediated Membranoproliferative Glomerulonephritis After Kidney Transplantation: Challengesand Opportunities José Enrique Ruiz-Cabello 1, Hernando Trujillo 1, Teresa Cavero 1, Amado Andrés 1, Manuel Praga2 and Fernando Caravaca-Fontán3 1Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain; 2Department of Medicine, Complutense University, Madrid, Spain; and 3Department of Nephrology, Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain Recurrent C3 glomerulopathy (C3G) and primary immune complex–mediated membranoproliferativeglomerulonephritis (IC-MPGN) remain major causes of kidney allograft dysfunction and loss. Their pathogenesis involves genetic susceptibility, acquired complement dysregulation, and transplant-related triggers, yet no clear validated predictors of recurrence exist. Recurrence rates after kidney transplantation frequently exceed 60% and are associated with progression to graft failure. Early detection, often achievable through protocol biopsies, offers an opportunity for timely intervention, although histologic recognition of early recurrence can be challenging. Comprehensive pretransplant evaluation, including genetic and molecular complement testing and screening for monoclonal gammopathies, may refine risk stratification. Conventional treatments, including intensified immunosuppression, rituximab, and plasma exchange, have shown limited and inconsistent efficacy. Conversely, complement-targeted therapies have yielded promising outcomes. Although eculizumab remains the most extensively studied agent, emerging proximal complement inhibitors such as iptacopan and pegcetacoplan have shown encouraging efficacy in both native and recurrent disease. However, optimal timing, prophylactic use, and long-term safety in transplant recipients remain uncertain. In this review, we outline the clinical spectrum, key diagnostic and therapeutic challenges, and emerging treatment strategies for recurrent C3G and IC-MPGN, highlighting advances that may ultimately improve graft survival and patient outcomes. Kidney Int Rep (2026) 11, 103682; [https://doi.org/10.1016/j.ekir.2025.11.008](https://doi.org/10.1016/j.ekir.2025.11.008) KEYWORDS: C3 glomerulopathy; immune-complex membranoproliferative glomerulonephritis; kidney failure; kidney transplantation; recurrence © 2025 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BYNC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/)). C 3G is an ultrarare glomerular disease driven by dysregulation of the alternative complement pathway. 1,2 This aberrant activation leads to the deposition of C3 and its breakdown products within the glomeruli, triggering inflammation and progressive decline in kidney function.3 C3G is currently defined by dominant C3 staining on immunofluorescence of kidney biopsy, either in Correspondence: José E. Ruiz-Cabello Subiela, Department of Nephrology, Hospital Universitario 12 de Octubre, Glorieta de Málaga, 11, 28041 Madrid, Spain. E-mail: jeruizcabello@gmail. com; or Fernando Caravaca-Fontán, Department of Nephrology, Research Institute Hospital 12 de Octubre, Glorieta de Málaga, 11, 28041. Madrid, Spain. E-mail: [fcaravacaf@gmail.com](fcaravacaf@gmail.com) Received 9 September 2025; revised 28 October 2025; accepted 3 November 2025; published online 12 November 2025 isolation or markedly exceeding other immune reactants by $ 2 orders of magnitude.4 Electron microscopy further distinguishes C3G into 2 main subtypes: C3 glomerulonephritis (C3GN) and dense deposit disease (DDD) .5,6 Emerging evidence suggests that dysregulation of the complement system may play a pathogenic role in cases diagnosed as primary ICMPGN, where C3 and Ig deposits are present at similar intensities and no underlying systemic disease is identi

FAQs

Why does C3 glomerulopathy and IC-MPGN recur after kidney transplantation?

Recurrence is linked to genetic susceptibility, acquired complement dysregulation, and transplant-related triggers. Although mechanisms overlap, validated predictors are not well established.

How is early recurrence detection approached and what are the main difficulties?

Protocol biopsies may detect recurrence early and enable timely intervention. Histologic recognition of early recurrence can still be challenging.

What treatment options are discussed, and why are conventional therapies limited?

Conventional approaches such as intensified immunosuppression, rituximab, and plasma exchange have shown limited and inconsistent efficacy. Complement-targeted therapies show more promising outcomes.

What questions remain about complement-targeted prophylaxis and long-term use?

Despite encouraging results with agents like eculizumab and proximal inhibitors (iptacopan, pegcetacoplan), optimal timing, prophylactic use, and long-term safety in transplant recipients remain uncertain.

Sep 29, 2026

Uploaded by Levi