Chutani A, Norouzi S, Lerma EV. C3 glomerulopathy in transplant “like yet unlike native”: Pathophysiology, recent advances in therapeutics and evolving paradigms. World J Transplant 2026; 16(2): 117138 [DOI: 10.5500/wjt.v16.i2.117138]
Corresponding Author of This Article
Arun Chutani, MD, Assistant Professor, FACP, FASN, Renal Medicine, UMass Chan Medical School, UMass Memorial Medical Center, 55 Lake Avenue North, Worcester, MA 01655, United States. docarun26@gmail.com
Research Domain of This Article
Transplantation
Article-Type of This Article
review-article
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Transplant. Jun 18, 2026; 16(2): 117138 Published online Jun 18, 2026. doi: 10.5500/wjt.v16.i2.117138
C3 glomerulopathy in transplant “like yet unlike native”: Pathophysiology, recent advances in therapeutics and evolving paradigms
Arun Chutani, Sayna Norouzi, Edgar V Lerma
Arun Chutani, Renal Medicine, UMass Chan Medical School, UMass Memorial Medical Center, Worcester, MA 01655, United States
Sayna Norouzi, Department of Internal Medicine, Loma Linda University, Loma Linda, CA 92350, United States
Edgar V Lerma, University of Illinois at Chicago College of Medicine, Advocate Christ Medical Center, University of Illnois, Chicago, IL 60612, United States
Author contributions: Chutani A remains the main author regarding conceptualization and construct of the manuscript; Norouzi S and Lerma EV provided constructive feedback in organizing the manuscript in its present form.
AI contribution statement: Co-Pilot was used for grammar correction and sentence structure modification. The manuscript is not AI generated; it is self-written, but Co-pilot helped with grammar correction and sentence structure modification for improving coherence.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Arun Chutani, MD, Assistant Professor, FACP, FASN, Renal Medicine, UMass Chan Medical School, UMass Memorial Medical Center, 55 Lake Avenue North, Worcester, MA 01655, United States. docarun26@gmail.com
Received: December 2, 2025 Revised: February 10, 2026 Accepted: April 7, 2026 Published online: June 18, 2026 Processing time: 180 Days and 7.2 Hours
Abstract
This review provides an in-depth examination of the recurrence and management of glomerular diseases after kidney transplantation, with particular emphasis on C3 glomerulopathy (C3G). Among post-transplant glomerular diseases, C3G exhibits the highest recurrence rates, reported between 30% and 89% across studies. The review outlines the complex pathophysiology of C3G, driven by dysregulation of the complement system - whether from genetic variants, autoantibodies, monoclonal gammopathy, or other acquired factors. It highlights the diagnostic challenges posed by overlapping features with hemolytic uremic syndrome and membranoproliferative glomerulonephritis, as well as the difficulty in distinguishing complement overactivation from true regulatory failure. Key mechanisms of complement activation and the role of regulatory proteins are discussed, along with operative and clinical risk factors such as ischemia-reperfusion injury, delayed graft function, viral infections, and monoclonal gammopathy. The review describes the histopathologic spectrum of C3G in the allograft and underscores the importance of early protocol biopsies for timely detection. Management strategies include conservative measures, nonspecific immunosuppression, and emerging complement-targeted therapies. Recent Food and Drug Administration approvals of iptacopan and pegcetacoplan represents major advances. The review concludes by emphasizing personalized medicine, improved biomarkers, comprehensive genetic and autoantibody testing, and continued research to refine surveillance and treatment strategies for transplant recipients with C3G.
Core Tip: C3 glomerulopathy is the most frequent recurrent glomerular disease after kidney transplantation, with recurrence rates up to 90%. Its pathogenesis is driven by alternative complement pathway dysregulation, influenced by genetic mutations, autoantibodies, monoclonal gammopathy, and transplant-specific triggers such as ischemia-reperfusion injury and viral infections. Histopathology in the allograft often shows subtler C3 deposition compared with native disease, underscoring the need for protocol biopsies. Traditional immunosuppression offers limited benefit, while novel complement-targeted therapies - including factor B inhibitors (iptacopan), C3 inhibitors (pegcetacoplan), and factor D inhibitors - represent a paradigm shift. Early case reports in transplant recipients demonstrate promising outcomes, highlighting the importance of personalized medicine and early intervention to preserve graft survival.
