2026-08-14 | Global research landscape of C3 glomerulopathy: A bibliometric analysis.
C3 glomerulopathy (C3G) is a rare, complement-mediated kidney disease with significant diagnostic and therapeutic challenges. Despite a growing number of publications, no study has comprehensively mapped the global research landscape. This bibliometric analysis aimed to evaluate publication trends, influential contributors, thematic evolution, and collaboration networks in C3G research from 1980 to 2025. A systematic bibliometric analysis was conducted using PubMed-indexed publications from 1980 - 2025 retrieved with predefined Boolean queries. Eligible articles included original research and reviews addressing the pathophysiology, diagnosis, and management of C3G. Bibliometric parameters were analyzed using the Bibliometrix package in R (v4.3) and VOSviewer (v1.6.20). Citation data were verified via Google Scholar. A total of 967 publications across 273 journals were identified. Research output increased exponentially after 2013, coinciding with the C3G Consensus Report and the rise of complement-targeted therapies. Pediatric Nephrology, Kidney International, and JASN were the leading publication venues. The United States, United Kingdom, and Italy were the most productive countries, with emerging contributions from China, India, and Türkiye. S. Sethi was the most prolific author (24 papers). Keyword co-occurrence and citation network analyses demonstrated a thematic shift from morphologic classification ("dense deposit disease") toward molecular and therapeutic paradigms ("complement inhibition," "iptacopan," "pegcetacoplan"). Collaboration networks remained modest and regionally clustered. Global research on C3G has evolved from descriptive pathology toward precision complement therapeutics. However, significant geographical disparities persist, emphasizing the need for stronger international collaboration and equitable access to emerging complement inhibitors.
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2026-08-13 | Characterizing Properdin-Inhibited C3 Nephritic Factors in Patients with Complement-Mediated Kidney Diseases.
C3 glomerulopathy (C3G) and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) are severe complement-mediated kidney diseases. In a substantial proportion of these patients, C3 nephritic factors (C3NeFs) are detected; these autoantibodies stabilize the complement alternative pathway (AP) C3 convertase. Previous studies have investigated and distinguished properdin-dependent and properdin-independent C3NeFs. In this study, we investigated a distinct subset of C3NeFs that are exclusively active in the absence of properdin: properdin-inhibited C3NeFs. A two-step hemolytic AP convertase activity assay was employed to examine convertase activity in patient serum in the presence versus absence of properdin using the properdin inhibitor Salp20. In 7/16 patients and 1/23 healthy controls, who showed no convertase stabilization in full serum, convertase stabilization was observed upon properdin inhibition, indicating properdin-inhibited C3NeF activity. Consistent findings were obtained when purified patient Igs were added to properdin-depleted serum. Moreover, in an ELISA-based C3bBb binding assay, 6/7 patients with properdin-inhibited C3NeFs showed increased convertase binding, which decreased upon addition of properdin. Complement levels in patients with properdin-inhibited C3NeFs were not significantly different from those in the C3NeF-negative group, and properdin levels were generally within the refence range. In conclusion, our results support the existence of properdin-inhibited C3NeFs, thereby further expanding the functional heterogeneity of these autoantibodies. Although their functional relevance under physiological conditions remains unclear, these findings may have important implications for complement-targeted therapies, particularly strategies aimed at properdin inhibition, as the presence of these C3NeFs may predispose to unintended effects.
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2026-08-11 | Management of Recurrent C3 Glomerulopathy After Kidney Transplantation.
C3 glomerulopathy (C3G) is an ultra-rare, complement-mediated glomerular disease characterized by dysregulation of the alternative complement pathway and a high propensity for recurrence after kidney transplantation. Although kidney transplantation remains the optimal treatment for patients reaching kidney failure, post-transplant recurrence continues to be a major cause of graft dysfunction and loss. Over the past decade, improved histopathologic recognition and the increasing adoption of protocol biopsies have revealed that C3G frequently recurs early after transplantation, often in a subclinical form. At present, no validated clinical, genetic, or functional biomarkers reliably predict recurrence, and preventive strategies remain unproven. Consequently, from our standpoint, management of recurrent C3G requires a pragmatic, surveillance-driven approach rather than prophylactic intervention. In this review, we provide a practical framework for managing recurrent C3G after kidney transplantation, from transplant candidacy and pre-transplant evaluation to post-transplant monitoring and therapeutic decision-making. We discuss the role of protocol biopsies, the limitations of conventional immunosuppression, and the emerging place of proximal complement inhibitors. Finally, we highlight several unmet needs that continue to limit optimal care, including persistent uncertainty about therapeutic goals, management of subclinical histologic recurrence, and interpretation of treatment response. This review reflects a transplant-centered clinical perspective aimed at supporting nephrologists in real-world decision-making.
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2026-08-04 | Complement-targeted therapies for C3 glomerulopathy and atypical hemolytic uremic syndrome: a time-limited rapid systematic review with narrative synthesis
C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS) are rare complement-mediated kidney diseases with differing injury sites and therapeutic targets. We conducted a time-limited rapid systematic review to synthesize clinical evidence on complement-targeted therapies. Rapid reviews streamline traditional systematic review methods to provide timely evidence for decision-making in situations where new regulatory approvals or clinical developments create an urgent need for synthesized evidence. The abbreviated timeframe was chosen to inform clinical practice following the March 2025 FDA approval of iptacopan and the July 2025 FDA approval of pegcetacoplan for C3G, at a time when clinicians required timely guidance on emerging therapeutic options. Seven databases were searched from inception to 24 April 2026, supplemented by Google Scholar, ClinicalTrials.gov , and congress abstracts. Chinese databases were searched post hoc ; no additional eligible studies were identified. Risk of bias was assessed with RoB 2, ROBINS-I, or JBI checklist; certainty of evidence was summarized using GRADE. Narrative synthesis without meta-analysis was performed due to substantial heterogeneity. Thirty-eight studies were included (14 C3G, 22 aHUS, 2 both). In aHUS, uncontrolled observational evidence indicates that anti-C5 therapy is associated with haematologic remission in many patients, but causal inference is limited by lack of randomized or concurrent controlled data. The largest prospective single-arm study (Legendre et al. n = 37) reported 80% TMA-free status at 26 weeks. Real-world cohorts corroborated these findings, though estimates are subject to selection bias and confounding by indication. In C3G, eculizumab showed heterogeneous responses. The APPEAR-C3G trial (Kavanagh et al. n = 74) demonstrated that iptacopan achieved a 35.1% relative reduction in 24 h urine protein-to-creatinine ratio (UPCR) at 6 months vs. placebo ( P = 0.0014). The VALIANT trial (Fakhouri et al. n = 124), now published in the New England Journal of Medicine, reported that pegcetacoplan reduced proteinuria by 68% at 26 weeks vs. placebo and achieved C3c clearance on biopsy in 71% of patients. Serious meningococcal infection remains a major safety concern. Based on low-certainty, non-randomized evidence, anti-C5 therapy in aHUS is associated with haematologic remission and renal recovery. In C3G, terminal complement blockade evidence remains weak, whereas factor B inhibition has emerging randomized evidence for short-term proteinuria reduction. Biomarker-guided patient selection and standardized outcomes should be priorities. This review employed narrative synthesis without meta-analysis; readers should not interpret reported percentages as pooled estimates. PROSPERO Registration CRD420261364711 (rapid registration, 9 April 2026).
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2026-07-28 | Therapeutic Evaluation of a C3-Targeting Small Nucleic Acid Drug in a Spontaneous Humanized C3 Glomerulopathy Mouse Model 2256845
Abstract Introduction Complement component C3 is central to the activation of the alternative pathway (AP), and its dysregulation drives C3 glomerulopathy, a severe renal autoimmune disease that lacks effective therapies. Methods To enable translational studies, we established a humanized C3G model, B6-hC3 mC3 KO, which overexpresses human C3 while lacking the endogenous murine C3. These mice spontaneously develop progressive glomerulopathy resembling human C3G pathology. Small nucleic acid drugs were administered to mice to evaluate drug efficacy. Results The disease phenotype observed in humanized C3 transgenic mice appears to arise from a dysfunctional interaction between human C3 protein and murine complement proteins, resulting in uncontrolled AP activation. Subcutaneous administration of C3-targeting small nucleic acid drugs effectively reduced serum C3 and plasma C3a levels, and downregulated the ratio of Ba (the activated fragment of complement factor B, CFB) to CFB, indicating suppression of AP hyperactivation. After 6 weeks of treatment, renal histology showed markedly reduced deposition of hC3 and diminished inflammatory cell infiltration. Conclusion B6-hC3 mC3 KO mice reproduce key immunopathological features of C3G and serve as a powerful platform for mechanistic studies and preclinical evaluation of complement-targeted therapeutics. Funding Source n/a Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)
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