C3 Glomerulopathy Research Articles

Acquired and genetic drivers of C3 and C5 convertase dysregulation in C3 glomerulopathy and immunoglobulin-associated MPGN.

Dysregulation of the alternative pathway of complement plays a central role in the pathophysiology of C3 Glomerulopathy (C3G). Various autoimmune and genetic factors targeting the alternative pathway have been associated to both C3G and primary Immunoglobulin-associated Membranoproliferative Glomerulonephritis (Ig-MPGN), suggesting shared pathophysiological mechanisms. This review highlights the wide range of disease drivers identified that mainly target components or protein complexes of the alternative pathway, both in C3G and Ig-MPGN. Nephritic factors, which constitute a heterogeneous group of autoantibodies targeting the C3 or the C5 convertase, are the most common abnormalities. Monoclonal gammopathies are frequent in aging adults. They may promote complement activation and have in some cases also found to target alternative pathway regulatory proteins. Additionally, some patients with C3G and Ig-MPGN carry rare variants in genes encoding complement activating or regulating proteins of the alternative pathway. This review provides an informative overview of pathogenetic mechanisms associated with each abnormality, acting at different steps in the complement cascade. The diversity of targets involved in the C3G pathophysiology suggests the potential benefit of therapeutical approaches tailored to the underlying disease drivers, with a pivotal impact upstream or at the level of the C3 or C5 convertase activity.

Acquired and genetic determinants of disease phenotype and therapeutic strategies in C3 glomerulopathy and immunoglobulin-associated MPGN.

C3 glomerulopathy (C3G), a prototype of complement mediated disease, is characterized by significant heterogeneity, not only in terms of clinical, histological and biological presentation but also of prognosis, and response to existing therapies. Recent advancements in understanding the factors responsible for alternative pathway dysregulation in the disease have highlighted its even more complex nature. Here, we propose a reexamination of the diversity of C3G presentations in light of the drivers of complement activation. Autoantibodies targeting complement proteins, genetic abnormalities in complement genes and monoclonal immunoglobulins are now well-known to drive disease occurrence. This review discusses how these drivers contribute to the heterogeneity in disease phenotype and outcomes, providing insights into tailored diagnostic and therapeutic approaches. In recent years, a broad spectrum of complement inhibitory therapies has emerged, soon to be available in clinical practice. The recognition of specific clinical, biological, and histological patterns associated with different forms of C3G is crucial for personalized management, particularly treatment strategies.

The Difficulties of Treating Complement-3–Mediated Glomerulopathy

Background: C3 glomerulopathy (C3G) is a rare disease affecting the complement alternative pathway, categorized into dense deposit disease and C3 glomerulonephritis. Dense deposit disease predominantly affects younger individuals, while C3 glomerulonephritis tends to manifest in older populations. The diseases are characterized by dysregulation of the complement alternative pathway, leading to the deposition of complement components in the glomeruli and subsequent renal dysfunction. Notably, the incidence of C3G in the United States is low, with 1–3 cases per 1,000,000 and a prevalence of 5 cases per 1,000,000. Areas of Uncertainty: Numerous uncertainties persist in comprehending the etiology and pathophysiology of C3G. While biomarkers such as C3 nephritic factor, autoantibodies, and relevant genetic mutations have been identified, their pathogenicity and clinical utility remain unclear. Standard workups involve complement assays and autoantibody panels, yet the definitive diagnostic test remains a kidney biopsy. Nuanced challenges lie in deciphering the sensitivity and specificity of these diagnostic tools, especially in the presence of phenotypical variations among individuals. Therapeutic Advancement: Current therapeutic approaches, albeit lacking robust evidence, encompass a spectrum ranging from supportive care to targeted B-cell therapy and immunosuppression with mycophenolate mofetil and glucocorticoids. For severe and refractory cases, the monoclonal antibody eculizumab, targeting C5 in the complement cascade, is recommended. These treatments, while offering some relief, pose challenges related to their cost and obtaining insurance approval. Exploratory avenues delve into the potential of plasma exchange and innovative treatments such as oral complement inhibitors, reflecting the ongoing quest for effective therapeutic modalities. Trials investigating various complement inhibitors underscore the dynamic landscape of therapeutic advancements in C3G management. Conclusion: In conclusion, the article highlights the complexities of C3G management. The need for further understanding, large-scale trials, and ongoing investigations into disease etiology and pathophysiology is emphasized.

C3 Glomerulopathy: A Current Perspective in an Evolving Landscape

Background: C3 Glomerulopathy (C3G) is a heterogenous disease characterized by dysregulation of the complement alternative pathway (AP). Within 10 years of a diagnosis, roughly 50% of patients with C3G will progress to end stage kidney disease (ESKD). Historically, treatment options have been limited to nonspecific immune suppression with suboptimal response rates to recommended therapies. Advances in immunology and the emergence of novel complement targeted therapies have shifted the focus toward identifying the distinct underlying etiologies of C3G. Summary: In this review, we provide a description of the current landscape and challenges faced in tbe classification, evaluation, and treatment of patients with C3G. Key Message: C3G can be broadly separated into four distinct groups: (1) Genetic mutations/variants, (2) Autoimmune/Acquired auto-antibodies, (3) Monoclonal immunoglobulin associated C3G (MIg-C3G), and (4) C3G without an identified cause. Therapy directed towards the underlying pathogenetic cause of disease may improve outcomes in a disease in which current treatment options are largely ineffective.

C3 glomerulopathy: a kidney disease mediated by alternative pathway deregulation.

C3 glomerulopathy (C3G) is an ultra-rare complement-mediated kidney disease caused by to the deregulation of the alternative pathway (AP) of proximal complement. Consequently, all effector loops of the complement are active and can lead to pathologies, such as C3a- and C5a-mediated inflammation, C3b opsonization, surface C3b-mediated AP C3 convertase assembly, C3 cleavage product deposition in the glomerulus, and lytic C5b-9/MAC cell damage. The most common pathologic mechanisms are defective chronic alternative pathway deregulation, mostly occurring in the plasma, often causing C3 consumption, and chronic complement-mediated glomerular damage. C3G develops over several years, and loss of renal function occurs in more than 50% of patients. C3G is triggered by both genetic and autoimmune alterations. Genetic causes include mutations in individual complement genes and chromosomal variations in the form of deletions and duplications affecting genes encoding complement modulators. Many genetic aberrations result in increased AP C3 convertase activity, either due to decreased activity of regulators, increased activity of modulators, or gain-of-function mutations in genes encoding components of the convertase. Autoimmune forms of C3G do also exist. Autoantibodies target individual complement components and regulators or bind to neoepitopes exposed in the central alternative pathway C3 convertase, thereby increasing enzyme activity. Overactive AP C3 convertase is common in C3G patients. Given that C3G is a complement disease mediated by defective alternative pathway action, complement blockade is an emerging concept for therapy. Here, we summarize both the causes of C3G and the rationale for complement inhibition and list the inhibitors that are being used in the most advanced clinical trials for C3G. With several inhibitors in phase II and III trials, it is expected that effectice treatment for C3G will become availabe in the near future.

C3 glomerulopathy is highly prevalent in French Polynesia

ObjectiveTo compare the natural history of C3 glomerulopathy (C3G) to acute post-infectious glomerulonephritis (APIGN) in a cohort of patients with a relative homogeneity of environment conditions and genetic background. MethodsWe retrospectively reviewed the characteristics of all patients with biopsy proven C3G or APIGN referred in 2013–2019 to the only renal unit in French Polynesia. ResultsPoint prevalence of C3G is ∼23 cases per 100,000 inhabitants. A recurrent variation of CFI (p.Arg406His) was identified at the heterozygous state in 4/8 (50 %) patients with C3G but its pathogenicity remain elusive. Characteristics at presentation and kidney outcomes were roughly similar between C3G (n = 16) and APIGN (n = 20), excepted for the presence of humps on kidney biopsy. ConclusionsC3G is highly prevalent in French Polynesia suggesting specific genetic or environmental susceptibility factors. Systematic diagnosis workflow should be proposed to all patients with C3 predominant glomerulonephritis.

Late Recurrence of C3 Glomerulopathy After SARS-CoV-2 Infection in a Long-Term Kidney Transplant Recipient: A Case Report

Late Recurrence of C3 Glomerulopathy After SARS-CoV-2 Infection in a Long-Term Kidney Transplant Recipient: A Case Report

Childhood onset C3 glomerulopathy: recurrence after kidney transplantation-a case series.

C3 Glomerulopathy (C3G) is a complement-mediated disease, with predominant C3 deposits, where pathogenic genetic variants in complement system components and circulating autoantibodies result in loss of control of the alternative pathway, have been described. A high incidence of disease recurrence including graft failure has been reported after kidney transplantation (KTx). Currently treatment modalities for preventing and treating post KTx C3G recurrence (plasma exchange, rituximab and eculizumab) in adults have yielded inconsistent results. Data on post KTx C3G recurrence in childhood-onset C3G is still unknown. A comprehensive case study of patients diagnosed with C3G as children or adolescents, who underwent KTx between the years 2015-2023. Data collected included complement workup, treatment modalities, and outcomes. 19 patients with C3G were identified during the study period. Five patients developed ESRD and received a kidney transplant. C3G recurrence was diagnosed post KTx in 100% of patients. Graft function improved in 3 of these patients (two with anti-factor H antibodies) after eculizumab treatment, one patient reached graft failure 9 months after transplantation despite eculizumab, recieved a second successful transplantation with pre-emptive eculizumab treatment and one patient showed histologic signs of disease recurrence without clinical signs. C3G recurrence after KTx in patients diagnosed as children or adolescents may be higher than previously described. Treatment with eculizumab is beneficial in some patients. New treatments are needed for improving post-transplant outcome in patients with C3G.

Outcome of Patients Transplanted for C3 Glomerulopathy and Primary Immune Complex-Mediated Membranoproliferative Glomerulonephritis

IntroductionAround 50% of C3 glomerulopathy and primary immune-complex-mediated membranoproliferative glomerulonephritis (C3G, IC-MPGN) patients reach kidney failure at 10 years after diagnosis. Since these patients are generally young, the majority will be listed for kidney transplantation. However, reported outcomes in patients transplanted for C3G and IC-MPGN are heterogeneous and conflicting, as they are mainly based on retrospective monocentric studies. We thus aimed to provide detailed multicenter data on these patients, taking advantage of the ongoing nationwide Swiss Transplant Cohort Study. MethodsWe analyzed patient and graft outcome, including the risk of graft loss in relation to recurrence of glomerulopathy. ResultsForty-one (10 C3G, 31 IC-MPGN) transplanted recipients were included with a mean age at transplantation of 48+16 years. Living donation provided 53% of the organs. During a mean follow-up of 4.7 years, 7 patients (4 C3G, 3 IC-MPGN) presented disease recurrence with a mean time to recurrence of 1.2 years. New-onset or rapidly increasing proteinuria was an early marker of recurrence, preceding significant decline in eGFR. Following recurrence, 28% lost their graft, compared to 11% of patients without recurrence. Disease recurrence was the primary cause of graft loss in all patients. Finally, 14% of patients died during follow-up. ConclusionThis study provides important insights into the epidemiology and outcome of C3G and IC-MPGN patients and their grafts after kidney transplantation. The data also suggest that proteinuria may serve as an early biomarker of disease recurrence and should be considered in patient management as well as an endpoint in current clinical trials using novel complement modulators.

Efficacy of Pegcetacoplan in Children with C3 Glomerulopathy

Efficacy of Pegcetacoplan in Children with C3 Glomerulopathy

Health Care Resource Utilization (HCRU) Burden in C3 Glomerulopathy (C3G) in the United States: A Retrospective Linked Electronic Medical Records (EMR) and Claims Database Analysis

Health Care Resource Utilization (HCRU) Burden in C3 Glomerulopathy (C3G) in the United States: A Retrospective Linked Electronic Medical Records (EMR) and Claims Database Analysis

Anti-factor H autoantibodies in patients with lupus nephritis

IntroductionLupus nephritis (LN) is a disease marked by autoantibodies against complement components. Autoantibodies against negative complement regulator factor H (anti-FH) are prevalent in aHUS, are associated with deletion of factor H-related protein 1 (FHR1) gene, and have overt functional consequences. They are also observed in C3 glomerulopathies. The frequency and relevance of anti-FH in LN are poorly studied. AimThe aim of our investigation was to screen for the presence of anti-FH and FHR1 gene deletion in a cohort of LN patients and to evaluate their association with LN activity. MethodELISA test and Western blot for detection of anti-FH and FHR1 deletion were used, respectively. Patients’ clinical and laboratory parameters regarding anti-FH role were processed by statistical analysis. ResultsAnti-FH were found at low level in a small number of LN patients – 11.7% (7/60) and were not associated with deletion of FHR1. Anti-FH did not correlate with ANA titers, anti-dsDNA, C3/C4 hypocomplementemia, eGFR, proteinuria, or active urinary sediment in LN patients. A weak correlation was found between anti-FH and anti-C3 levels. Anti-FH were linked with endocapillary proliferation and histological activity index. Four anti-FH positive patients had severe to moderate LN as per the BILAG renal score. ConclusionsAnti-FH autoantibodies are an accessory finding in LN and are more likely to manifest during the active phase of the disease. Due to their low frequency and plasma levels, they do not seem suitable for routine laboratory investigation in patients with LN.

Correlations in Histology and Complement Biomarkers in C3 Glomerulopathy

Correlations in Histology and Complement Biomarkers in C3 Glomerulopathy

C3 Glomerulopathy: A Pediatric and Adult Case Series in New Mexico

C3 Glomerulopathy: A Pediatric and Adult Case Series in New Mexico

Long-Term Safety and Efficacy of Pegcetacoplan in Patients with C3 Glomerulopathy or Primary Immune-Complex Membranoproliferative Glomerulonephritis: The Long-Term VALE Extension Study

Long-Term Safety and Efficacy of Pegcetacoplan in Patients with C3 Glomerulopathy or Primary Immune-Complex Membranoproliferative Glomerulonephritis: The Long-Term VALE Extension Study

Design of an Observational, Longitudinal Data Platform of Patients with C3 Glomerulopathy (C3G) and Idiopathic Immune-Complex Membranoproliferative Glomerulonephritis (IC-MPGN) in the United States

Design of an Observational, Longitudinal Data Platform of Patients with C3 Glomerulopathy (C3G) and Idiopathic Immune-Complex Membranoproliferative Glomerulonephritis (IC-MPGN) in the United States

Clinical and Histological Predictors of Outcomes in C3 Glomerulopathy

Clinical and Histological Predictors of Outcomes in C3 Glomerulopathy

Proteinuria as a Surrogate Predictor of Kidney Failure in Both C3 Glomerulopathy and Primary Immune-Complex Membranoproliferative Glomerulonephritis

Proteinuria as a Surrogate Predictor of Kidney Failure in Both C3 Glomerulopathy and Primary Immune-Complex Membranoproliferative Glomerulonephritis

C3 Nephrotic Factor at Diagnosis Is Associated with Better eGFR Preservation in Patients with C3 Glomerulopathy (C3G): Findings from the European Rare Kidney Disease Registry (ERKReg)

C3 Nephrotic Factor at Diagnosis Is Associated with Better eGFR Preservation in Patients with C3 Glomerulopathy (C3G): Findings from the European Rare Kidney Disease Registry (ERKReg)

Expanding the Use of Surface Plasmon Resonance (SPR) for Characterizing Nephritic Factors in Patients with C3 Glomerulopathy (C3G)

Expanding the Use of Surface Plasmon Resonance (SPR) for Characterizing Nephritic Factors in Patients with C3 Glomerulopathy (C3G)