RARE DISEASE
Primary membranoproliferative glomerulonephritis
Primary membranoproliferative glomerulonephritis
Primary membranoproliferative glomerulonephritis
Synonyms: Mesangiocapillary glomerulonephritis, Primary MPGN
Synonyms: Mesangiocapillary glomerulonephritis, Primary MPGN
Synonyms: Mesangiocapillary glomerulonephritis, Primary MPGN
Drug discovery
2
drugs
With orphan designations
Overview
Primary membranoproliferative glomerulonephritis (MPGN) is a rare glomerular disease characterized by mesangial hypercellularity, endocapillary proliferation, and glomerular basement membrane thickening on biopsy. It encompasses C3 glomerulopathy (complement-mediated) and immunoglobulin-mediated MPGN, differentiated via immunofluorescence [1][6][12]. Patients often present with nephrotic/nephritic syndromes or asymptomatic proteinuria/hematuria, with variable progression to end-stage kidney disease (ESKD) [2][6]. Etiology involves immune complex deposition or complement dysregulation, with secondary causes excluded [1][16].
Population
Burden
~27% progress to ESKD within 10 years, with recurrence rates post-transplant reaching 15–30% [2][12].
High morbidity: persistent proteinuria, hypertension, and infection risk due to immunosuppression [6][11].
Limited targeted therapies underscore reliance on supportive care and off-label regimens [3][16].
Therapies
First-line: Renin-angiotensin system inhibitors (e.g., ACEi/ARBs) for proteinuria and blood pressure control [3][12].
Immunosuppression: Corticosteroids, cyclosporine, or mycophenolate mofetil (more common in younger patients) [2][11].
Investigational: Anti-complement therapies (e.g., eculizumab) show mixed efficacy; clinical trials targeting C3/C5 are ongoing [3][12].
Categories: rare genetic diseases, rare renal diseases, rare transplant-related disorders
Research Papers
508 drug discovery papers about Primary membranoproliferative glomerulonephritis, with 2 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
508 drug discovery papers about Primary membranoproliferative glomerulonephritis, with 2 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-09 | Remission of Nephrotic Proteinuria after Liver Transplantation in a Case of Abernethy Malformation Type Ib and Membranoproliferative Glomerulonephritis.
Abernethy malformation is a rare congenital vascular anomaly defined by the absence or severe hypoplasia of the portal vein, resulting in portosystemic shunting. The metabolic and immunologic consequences such as hepatic encephalopathy and pulmonary complications are well recognized. However, renal involvement of Abernethy malformation has been reported rarely . We report a 13-year-old boy who presented with severe anemia, pneumonia and nephrotic-range proteinuria (14.18 g/24 h). Imaging demonstrated type Ib Abernethy malformation, with complete agenesis of the portal vein and direct drainage into the inferior vena cava. Kidney biopsy showed immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) with a"full house" immunofluorescence pattern and hypocomplementemia. Biomarkers for autoimmune disease, infection and monoclonal gammopathy were negative. The patient showed a limited response to methylprednisolone, cyclophosphamide and intravenous immunoglobulin. However, proteinuria declined to 1.2 g/24 h four weeks after liver transplantation,. The complement and hemoglobin levels also normalized. The patient currently has negative proteinuria on tacrolimus monotherapy. This case illustrates a potential association between Abernethy malformation and membranoproliferative glomerulonephritis (MPGN). It also highlights the importance of vascular imaging in patients with unexplained glomerulonephritis and hypocomplementemia accompanied by hepatic anomalies.
2026-07-03 | Pivotal Clinical Trials in C3 Glomerulopathy: answers and remaining uncertainties.
Complement 3 glomerulopathy (C3G) and primary immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) are ultra-rare glomerular diseases driven by dysregulation of the complement system, most commonly involving the alternative pathway. Recent advances in the understanding of disease pathogenesis have enabled the development of targeted complement therapies. The publication of pivotal phase 3 trials evaluating proximal complement inhibitors -iptacopan, a selective factor B inhibitor, and pegcetacoplan, a C3 inhibitor- marks a turning point in the management of C3G and IC-MPGN. Both agents demonstrated clinically meaningful reductions in proteinuria and stabilization of kidney function, establishing proof of efficacy. Despite these advances, important uncertainties remain. Key unresolved issues include optimal patient selection, timing and duration of therapy, treatment sequencing, monitoring strategies, and long-term kidney outcomes. Conventional immunosuppressive approaches provide inconsistent benefit and do not directly address complement dysregulation, while validated biomarkers to guide complement blockade are lacking. Additional challenges relate to treatment discontinuation, management of special populations, and health-system implementation. This review critically appraises the evidence from recent pivotal trials, highlighting both their transformative impact and the questions they raise. We emphasize the need for long-term outcome studies, precision-based therapeutic strategies, and pragmatic real-world data. Ultimately, the challenge ahead is not whether complement inhibition is effective but how best to deploy these therapies to maximize durable benefit, minimize risk, and ensure equitable access.
2026-06-29 | Natural History and Progression of Recurrent C3 Glomerulopathy and Primary Immune-Complex Membranoproliferative Glomerulonephritis in Kidney Transplantation
Background: C3 glomerulopathy (C3G) and primary immune complex–mediated membranoproliferative glomerulonephritis (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 estimated glomerular filtration rate (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%, DDD 12%, IC-MPGN 28%). 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/day and eGFR lowering steeper than –5 mL/min/1.73 m 2 /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 biological heterogeneity. Longitudinal eGFR and proteinuria provide powerful prognostic information, and clinically meaningful thresholds (>1 g/day time-averaged proteinuria; eGFR slope steeper than –5 mL/min/1.73 m 2 /year) refine risk stratification. Dynamic biomarkers may serve as surrogate endpoints, underscoring the need for prospective validation with emerging proximal complement therapies.
2026-06-29 | Mechanism-centered target discovery across glomerulonephritis phenotypes: an integrative multi-omics study.
Glomerulonephritis (GN) comprises a heterogeneous group of immune-mediated kidney disorders with substantial biological and clinical diversity. Current treatment still relies largely on broad immunosuppression, underscoring the need for mechanism-informed target discovery across GN phenotypes. We performed a program-guided integrative multi-omics study by combining cis-expression quantitative trait loci and cis-protein quantitative trait loci with GN genome-wide association datasets from UK Biobank, the GWAS Catalog, and FinnGen. Candidate genes were organized into four predefined mechanistic programs: cytokine/TNF signaling, cell-cycle/senescence-repair balance, complement/innate immune activation, and regulated cell-death/redox stress. Six GN-related outcomes were analyzed. Bayesian colocalization, cross-dataset meta-analysis, mouse knockout annotation, drug-repurposing assessment, network pharmacology, and rule-based evidence scoring were used to refine target prioritization. Integrative screening identified 42 transcriptomic and 12 proteomic putative targets, with the strongest enrichment in non-proliferative glomerulonephritis and primary membranoproliferative glomerulonephritis. Bayesian colocalization supported PPP2R1B in non-proliferative glomerulonephritis, SOD1 in IgA nephropathy, and CDK4 in primary membranoproliferative glomerulonephritis. Among 42 transcriptomic gene-outcome pairs taken forward, 11 were supported by cross-dataset meta-analysis. Proteomic meta-analysis supported several cross-dataset signals, including protective associations of ANXA5, GSR, and TNFRSF1B with glomerulonephritis. Across outcomes, complement/innate immunity and cytokine/TNF signaling formed the dominant shared backbone. After separating MHC-region signals for cautious interpretation, 31 non-MHC targets were retained for primary prioritization, with PPP2R1B, CDK4, and SOD1 comprising the top tier. This mechanism-centered integrative multi-omics study delineates shared and phenotype-enriched biological programs across the GN spectrum and identifies a prioritized set of candidate targets for future validation and therapeutic development.
2026-06-05 | Immune complex-mediated membranoproliferative glomerulonephritis following scabies infestation in a child: a rare association.
Scabies, caused by Sarcoptes scabiei var. hominis, is a common parasitic infestation in tropical regions. Although primarily dermatological, it can rarely trigger systemic complications such as immune complex-mediated membranoproliferative glomerulonephritis (MPGN). A 14-year-old boy presented with bilateral pedal edema, facial puffiness, and reddish urine for one week. Examination revealed pruritic papular lesions over the interdigital spaces, and microscopy confirmed Sarcoptes scabiei infestation. Investigations showed nephrotic-range proteinuria (4.9 g/day), microscopic hematuria, and normal complement levels. Kidney biopsy demonstrated immune complex-mediated MPGN with crescent formation. The patient was treated with topical 5% permethrin and oral ivermectin for scabies, followed by corticosteroid pulses and monthly cyclophosphamide. Complete clinical and biochemical remission occurred within six months. This case highlights scabies as a potential trigger for immune complex-mediated glomerulonephritis through chronic antigenic stimulation. Scabies-associated MPGN, though rare, should be recognized as a treatable cause of immune-mediated kidney injury. Early diagnosis and combined anti-parasitic and immunosuppressive therapy can achieve complete remission.
proteins
2024-02-01 | C3G and Ig-MPGN-treatment standard.
Among the broad spectrum of membranoproliferative glomerulonephritis (MPGN), immunofluorescence distinguishes C3 glomerulopathy (C3G), with predominant C3 deposits, and immunoglobulin-associated MPGN (Ig-MPGN), with combined C3 and Ig. However, there are several intersections between C3G and Ig-MPGN. Primary C3G and Ig-MPGN share the same prevalence of low serum C3 levels and of abnormalities of the alternative pathway of complement, and patients who present a bioptic pattern of Ig-MPGN at onset may show a C3G pattern in a subsequent biopsy. There is no specific therapy for primary C3G and Ig-MPGN and prognosis is unfavourable. The only recommended indications are inhibitors of the renin-angiotensin system, lipid-lowering agents and other renoprotective agents. The other drugs used currently, such as corticosteroids and mycophenolate mofetil, are often ineffective. The anti-C5 monoclonal antibody eculizumab has been tested in several patients, with mixed results. One reason for the uncertainty is the extremely variable clinical course, most likely reflecting a heterogeneous pathogenesis. An unsupervised clustering analysis that included histologic, biochemical, genetic and clinical data available at onset in patients with primary C3G and Ig-MPGN identified four clusters characterized by specific pathogenic mechanisms. This approach may facilitate accurate diagnosis and development of targeted therapies. Several trials are ongoing with drugs targeting different molecules of the complement cascade, however it is important to consider which component of the cascade may be the most appropriate for each patient. We review the current standards of treatment and discuss novel developments in the pathophysiology, diagnosis, outcome prediction and management of C3G and Ig-MPGN.
2018-08-22 | Complement regulation and kidney diseases: recent knowledge of the double-edged roles of complement activation in nephrology.
The complement activation system plays important roles to maintain homeostasis in the host and to fight foreign invaders to protect the host. Therefore, the complement system is considered a core part of innate immunity which also cross-talks to acquired immunity. In the history of nephrology, the complement system is familiar to us, because complement protein or fragment deposition, including C3, C4, C1q, and/or C4d, is routinely estimated by immunohistochemistry to diagnose renal pathologies. The relationships between pathological mechanisms and complement activation have been investigated for renal diseases such as post-infectious glomerulonephritis, lupus nephritis, and primary membranoproliferative glomerulonephritis, which are usually accompanied by hypocomplementemia. However, unregulated complement activation in local areas might be associated with progression of various renal injuries even in the normocomplementemic patient. Recently, attention has focused on dysfunction of complement regulation in various diseases including renal diseases such as atypical hemolytic uremic syndrome and C3 glomerulopathy. Some mechanisms associated with complement activation in these diseases were clarified. In addition, lots of anti-complement agents were developed and some of the agents have become clinically available. Now, anti-complement therapies represent a realistic choice of therapeutic approaches for complement-related diseases. Research on roles of complement activation is proceeding into new stages in the field of nephrology and in other fields involving both basic and clinical research. We herein summarize relationships between the complement activation and regulation systems, their physiological effects and roles in maintenance of homeostasis in the host, and how dysregulation of the complement system triggers disease, especially renal disease.
2017-09-05 | Chronic hepatitis C virus (HCV) increases the risk of chronic kidney disease (CKD) while effective HCV treatment decreases the incidence of CKD
We assessed the risk of chronic kidney disease (CKD) in chronic hepatitis C virus (HCV)‐infected patients and the incidence reduction of CKD after receipt of HCV treatment. We also evaluated the risk of membranoproliferative glomerulonephritis (MPGN) and cryoglobulinemia in chronic HCV patients. A retrospective cohort analysis of the Truven Health MarketScan Database (2008‐2015) in the United States was conducted. In a cohort of 56,448 HCV‐infected patients and 169,344 propensity score (1:3)–matched non‐HCV patients, we examined the association of HCV infection with the incidence of CKD. Of 55,818 HCV patients, 6.6 % (n = 3666), 6.3% (n = 3534), and 8.3% (n = 4628) patients received either interferon‐based dual, triple, or all‐oral direct acting antiviral agent therapy, respectively, whereas 79% of patients did not receive any HCV treatment. Cox proportional hazards models were used to compare the risk of developing CKD in HCV patients compared with non‐HCV patients and treated patients compared with untreated HCV patients. In a multivariate time‐varying Cox regression model, HCV‐infected patients had a 27% increased risk of CKD compared with non‐HCV patients (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.18‐1.37). Among HCV patients, individuals who received the minimally effective HCV treatment for dual, triple, or all‐oral therapy had a 30% decreased risk of developing CKD (HR, 0.70; 95% CI, 0.55‐0.88). In addition, HCV‐infected patients experienced a twofold and a nearly 17‐fold higher risk of MPGN (HR, 2.23; 95% CI, 1.84‐2.71) and cryoglobulinemia (HR, 16.91; 95% CI, 12.00‐23.81) respectively, compared with non‐HCV patients. Conclusion: HCV‐infected individuals in the United States are at greater risk of developing CKD, MPGN, and cryoglobulinemia. Minimally effective treatment of HCV infection can prevent the development of CKD, although the association was not significant for all‐oral therapy. (H epatology 2018;67:492‐504).
2014-10-01 | The complement cascade and renal disease.
Serum complement cascade, a part of innate immunity required for host protection against invading pathogens, is also a mediator of various forms of disease and injury. It is activated by classical, lectin, and alternative pathways that lead to activation of C3 component by C3 convertases, release of C3b opsonin, C5 conversion and eventually membrane attack complex formation. The tightly regulated activation process yields also C3a and C5a anaphylatoxins, which target a broad spectrum of immune and non-immune cells. The review discusses the involvement of the complement cascade in kidney disease pathogenesis and injury. The role of the complement pathways in autoantibody-mediated forms of glomerulonephritis (lupus nephritis, anti-glomerular basement membrane disease, anti-neutrophil cytoplasmic autoantibody-induced or membranoproliferative glomerulonephritis, membranous nephropathy), C3 glomerulopathy, atypical forms of hemolytic uremic syndrome, ischemic-reperfusion injury of transplanted kidney, and antibody-mediated renal allograft rejection are discussed. The disturbances in complement activation and regulation with underlying genetics are presented and related to observed pathology. Also promising strategies targeting the complement system in complement-related disorders are mentioned.
2012-08-06 | A novel, dual role of CCN3 in experimental glomerulonephritis: pro-angiogenic and antimesangioproliferative effects.
In contrast to factors that promote mesangial cell proliferation, little is known about their endogenous inhibitors. During experimental mesangioproliferative nephritis, expression of the glomerular CCN3 (nephroblastoma overexpressed gene [NOV]) gene is reduced before the proliferative phase and increased in glomeruli and serum when mesangial cell proliferation subsides. To further elucidate its role in mesangioproliferative glomerulonephritis, CCN3 systemically was overexpressed by muscle electroporation in healthy or nephritic rats. This increased CCN3 serum concentrations more than threefold for up to 56 days. At day 5 after disease induction, CCN3-transfected rats showed an increase in glomerular endothelial area and in mRNA levels of the pro-angiogenic factors vascular endothelial growth factor and PDGF-C. At day 7, CCN3 overexpression decreased mesangial cell proliferation, including expression of α-smooth muscle actin and matrix accumulation of fibronectin and type IV collagen. In progressive nephritis (day 56), overexpression of CCN3 resulted in decreased albuminuria, glomerulosclerosis, and reduced cortical collagen type I accumulation. In healthy rat kidneys, overexpression of CCN3 induced no morphologic changes but regulated glomerular gene transcripts (reduced transcription of PDGF-B, PDGF-D, PDGF-receptor-β, and fibronectin, and increased PDGF-receptor-α and PDGF-C mRNA). These data identify a dual role for CCN3 in experimental glomerulonephritis with pro-angiogenic and antimesangioproliferative effects. Manipulation of CCN3 may represent a novel approach to help repair glomerular endothelial damage and mesangioproliferative changes.
antibodies
2026-06-22 | Natural History of C3 Glomerulopathy and Immune Complex-Associated Membranoproliferative Glomerulonephritis in Children.
C3 glomerulopathy (C3G) and immune complex-associated membranoproliferative glomerulonephritis (IC-MPGN) are rare complement-mediated kidney diseases with a high risk of progression to kidney failure. Little is known about the natural history of these diseases in children, limiting our understanding of risk factors for progressive kidney disease. Using a computable phenotype algorithm, a pediatric cohort with C3G or IC-MPGN was identified at seven institutions in PEDSnet, a national network of pediatric health systems which aggregate electronic health record data and collaborate on pragmatic research studies. Discrete data elements were captured from electronic health records and additional clinical and histopathologic data were extracted by standardized chart review by pediatric nephrologists. Biopsy diagnosis was classified as C3G or IC-MPGN by applying an algorithm based on immunofluorescence and electron microscopy and supplemented with manual chart review. Kaplan-Meier survival curves were utilized to compare the risk of reaching a composite kidney outcome of 50% reduction in estimated glomerular filtration rate (eGFR), initiation of maintenance dialysis, or kidney transplantation. Of 204 patients with MPGN identified by the computable phenotype algorithm and chart review, 159 could be further classified as C3G or IC-MPGN based on available biopsy data. There were no significant differences in baseline serum albumin, C3 level, urine protein/creatinine ratio, or eGFR between C3G or IC-MPGN. Patients with C3G and IC-MPGN had similar rates of progression to the composite kidney outcome, and a low serum C3 level at baseline was associated with this composite outcome. Using large-scale, real-world multi-institutional data, we investigated the natural history of a large contemporary cohort of children with MPGN. As patients classified as having C3G compared to IC-MPGN had similar baseline clinical characteristics and rates of progressive disease despite untargeted treatment approaches, the availability of newer complement-targeted agents hold the promise of benefit to this population.
2026-02-20 | A nephritic puzzle: C3-dominant glomerulonephritis as a sentinel of hidden autoinflammatory disease.
Membranoproliferative glomerulonephritis (MPGN) is among the most challenging glomerulonephritides to diagnose and manage, given its clinico-immunopathologic heterogeneity. Although recent advances have introduced new therapies for complement-mediated and immune-complex MPGN, a substantial subset of cases remains poorly understood and lacks effective treatment. We report a pediatric case of biopsy-confirmed C3-dominant MPGN without evidence of complement dysregulation, with disease flares triggered by febrile episodes. Genetic testing identified underlying hyper-IgD syndrome (HIDS), a rare autoinflammatory disorder characterized by recurrent fevers and immune dysregulation. The patient's MPGN was refractory to conventional immunosuppressive therapy but achieved remission with IL-1β blockade that targets HIDS. This case highlights the importance of considering alternative etiologies-including autoinflammatory diseases-in patients with MPGN when complement dysregulation is not evident.
2025-12-03 | Trial of Pegcetacoplan in C3 Glomerulopathy and Immune-Complex MPGN.
C3 glomerulopathy and primary immune-complex membranoproliferative glomerulonephritis (MPGN) generally result in glomerular C3 deposition and irreversible kidney damage. The efficacy and safety of pegcetacoplan, a C3 and C3b inhibitor, in persons with C3 glomerulopathy or primary immune-complex MPGN are unclear. We conducted a phase 3, double-blind, placebo-controlled trial involving adolescents and adults with C3 glomerulopathy or primary immune-complex MPGN, including those with native kidney disease and those with disease recurrence after transplantation. Patients were randomly assigned in a 1:1 ratio to receive pegcetacoplan or placebo. The primary end point was the log-transformed ratio of the urinary protein-to-creatinine ratio at week 26 as compared with baseline. A total of 124 patients underwent randomization. The change in proteinuria (as measured by the log-transformed ratio to baseline in the urinary protein-to-creatinine ratio) was significantly greater with pegcetacoplan than with placebo (geometric mean of the urinary protein-to-creatinine ratio, -67.2% [95% confidence interval {CI}, -74.9 to -57.2] vs. 2.9% [95% CI, -8.6 to 15.9]). The difference represents a relative reduction of 68.1% (95% CI, 57.3 to 76.2) as compared with placebo. In hierarchical testing of five secondary end points, significantly higher percentages of patients in the pegcetacoplan group than in the placebo group met the composite renal end-point criteria (stabilization of estimated glomerular filtration rate [eGFR] and ≥50% reduction in urinary protein-to-creatinine ratio) (49% vs. 3%) and had at least a 50% reduction in the protein-to-creatinine ratio (60% vs. 5%). Among 69 patients with evaluable kidney-biopsy samples, the change in the activity score of the C3 glomerulopathy histologic index did not differ significantly between the two groups; subsequent end points (decrease in C3 staining and change in eGFR) were not formally tested. Pegcetacoplan was not associated with more adverse events than placebo. No serious infections from encapsulated bacteria occurred; 1 patient receiving pegcetacoplan died from coronavirus disease 2019 pneumonia. No allograft rejection or loss occurred. Pegcetacoplan resulted in a significantly greater reduction in proteinuria than placebo among patients with C3 glomerulopathy or primary immune-complex MPGN. (Funded by Apellis Pharmaceuticals and Sobi [Swedish Orphan Biovitrum]; VALIANT ClinicalTrials.gov number, NCT05067127.).
2025-10-12 | Hierarchical clustering uncovered disease patterns and further untangled complexities in immune complex-mediated idiopathic MPGN and C3 glomerulopathy.
Membranoproliferative glomerulonephritis (MPGN) is currently stratified into complement C3 glomerulopathy (C3G) and immune complex-mediated MPGN (IC-MPGN). However, classification is subject to continued debate. Here, we applied hierarchical clustering to a much larger cohort of patients with C3G/IC-MPGN (295 individuals), extensively characterized for genetic and autoimmune complement abnormalities, with the goal of unraveling specific disease patterns. We also designed a user-friendly web application that with input of data at diagnosis could make cluster classification clinically applicable. Five clusters with unique phenotypic and complement profiles were identified. Cluster 1 and 2 patients showed systemic complement activation until C5. Consistently, C5 nephritic factor and anti-factor B antibodies were prevalent in these clusters. Cluster 2 was distinguished from cluster 1 for classical pathway activation markers in biopsy. Cluster 3 showed C3-restricted systemic complement activation associated with the prevalence of C3 nephritic factor. Cluster 4 and 5 patients shared a normal complement profile and intense glomerular C3 staining, consistent with solid-phase complement activation, but cluster 5 distinguished for the higher prevalence of genetic abnormalities. Cluster 4 patients had the highest incidence of kidney failure during follow-up, while cluster 1 had the best kidney prognosis. However, clusters 1 and 2 showed a high risk of post-transplant recurrence. Through our web application, we could visually compare the predicted profile of new patients with those of patients included in clustering analysis and assign these patients to different clusters. The cluster-based classification allows etiologic diagnosis of C3G/IC-MPGN and had better prognostic value than current approaches. Our proposed strategy may possibly guide anti-complement treatment.
2025-10-01 | #3363 Diagnostic gaps in C3G and ic-MPGN: findings of the CompCure study cohort
Abstract Background and Aims C3 glomerulopathy (C3G) and immune complex-mediated membranoproliferative glomerulonephritis (ic-MPGN) are chronic kidney disorders characterized by abnormal activation of the alternative complement pathway. The etiology of the conditions is heterogeneous and variably involves C3 activating auto-antibodies, alterations in complement regulating genes and activation of the terminal complement pathway. Classification by diagnostic biomarker panels has been proposed to improve outcome prediction. While currently available non-specific immunosuppressive and antiproteinuric therapies yield highly variable long-term disease outcomes, new treatments targeting individual components of the complement system are in development. These emerging novel therapeutic options increase the need for standardized, comprehensive diagnostic evaluation of C3G/ic-MPGN to empower rational, personalized treatment approaches. The European Rare Kidney Disease Reference Network (ERKNet) and the CompCure Association for complement-mediated diseases have recently established a large prospective registry study following adults and children with C3G/ic-MPGN. The CompCure project aims to explore the association of diagnostic biomarkers with treatment responsiveness and disease outcomes. Here, we analyzed the completeness of available complement diagnostic features and the detection rate of abnormalities in the study cohort. Method A total of 236 patients were analyzed, including 157 with C3G (141 C3GN, 16 DDD) and 70 with ic-MPGN, registered across 36 European nephrology referral centers (30 pediatric, 11 adult). Disease onset was during childhood in 70% of the patients. 77% of patients were enrolled within 6 months of diagnosis. The diagnosis was established by kidney biopsy with immunofluorescence and electron microscopy in all cases. Results At time of diagnosis, global CH50 and AP50 complement tests were conducted in 26% and 15% of cases, respectively. While serum C3 was tested in 71% and C4 in 69% of patients, other complement proteins were rarely assessed: Factor H in 17%, C5 in 3%, and Properdin in 2%. The membrane attack complex (sC5b-9) was measured in 32%, and Bb in 4%. Among autoantibodies, C3Nef was tested in 33%, anti-FH in 31%, anti-FB in 9%, anti-C3b in 11%, and C5Nef in 5% of patients. Genetic testing was performed in 56% of C3GN, 75% of DDD, and 15% of ic-MPGN patients. The assessment of core diagnostic features increased with time during the observation period: Conclusion The diagnostic evaluation of patients with C3G/ic-MPGN in European referral centers primarily relies on histopathological findings and serum C3 levels. Essential tests such as sC5b-9, C3Nef and other autoantibodies as well as complement gene screening are still performed in a minority of patients. Reasons for the incomplete diagnostic assessment may include the low number of specialized complement diagnostic laboratories in Europe, a lack of standardized diagnostic panels, high cost and long processing times. This gap in diagnostic practices hampers accurate disease classification and patient stratification for personalized treatment protocols. The CompCure cohort study will support participating sites to obtain standardized diagnostics in newly diagnosed patients with C3G/ic-MPGN.
small molecules
2026-08-09 | Remission of Nephrotic Proteinuria after Liver Transplantation in a Case of Abernethy Malformation Type Ib and Membranoproliferative Glomerulonephritis.
Abernethy malformation is a rare congenital vascular anomaly defined by the absence or severe hypoplasia of the portal vein, resulting in portosystemic shunting. The metabolic and immunologic consequences such as hepatic encephalopathy and pulmonary complications are well recognized. However, renal involvement of Abernethy malformation has been reported rarely . We report a 13-year-old boy who presented with severe anemia, pneumonia and nephrotic-range proteinuria (14.18 g/24 h). Imaging demonstrated type Ib Abernethy malformation, with complete agenesis of the portal vein and direct drainage into the inferior vena cava. Kidney biopsy showed immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) with a"full house" immunofluorescence pattern and hypocomplementemia. Biomarkers for autoimmune disease, infection and monoclonal gammopathy were negative. The patient showed a limited response to methylprednisolone, cyclophosphamide and intravenous immunoglobulin. However, proteinuria declined to 1.2 g/24 h four weeks after liver transplantation,. The complement and hemoglobin levels also normalized. The patient currently has negative proteinuria on tacrolimus monotherapy. This case illustrates a potential association between Abernethy malformation and membranoproliferative glomerulonephritis (MPGN). It also highlights the importance of vascular imaging in patients with unexplained glomerulonephritis and hypocomplementemia accompanied by hepatic anomalies.
2026-07-03 | Pivotal Clinical Trials in C3 Glomerulopathy: answers and remaining uncertainties.
Complement 3 glomerulopathy (C3G) and primary immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) are ultra-rare glomerular diseases driven by dysregulation of the complement system, most commonly involving the alternative pathway. Recent advances in the understanding of disease pathogenesis have enabled the development of targeted complement therapies. The publication of pivotal phase 3 trials evaluating proximal complement inhibitors -iptacopan, a selective factor B inhibitor, and pegcetacoplan, a C3 inhibitor- marks a turning point in the management of C3G and IC-MPGN. Both agents demonstrated clinically meaningful reductions in proteinuria and stabilization of kidney function, establishing proof of efficacy. Despite these advances, important uncertainties remain. Key unresolved issues include optimal patient selection, timing and duration of therapy, treatment sequencing, monitoring strategies, and long-term kidney outcomes. Conventional immunosuppressive approaches provide inconsistent benefit and do not directly address complement dysregulation, while validated biomarkers to guide complement blockade are lacking. Additional challenges relate to treatment discontinuation, management of special populations, and health-system implementation. This review critically appraises the evidence from recent pivotal trials, highlighting both their transformative impact and the questions they raise. We emphasize the need for long-term outcome studies, precision-based therapeutic strategies, and pragmatic real-world data. Ultimately, the challenge ahead is not whether complement inhibition is effective but how best to deploy these therapies to maximize durable benefit, minimize risk, and ensure equitable access.
2026-06-29 | Natural History and Progression of Recurrent C3 Glomerulopathy and Primary Immune-Complex Membranoproliferative Glomerulonephritis in Kidney Transplantation
Background: C3 glomerulopathy (C3G) and primary immune complex–mediated membranoproliferative glomerulonephritis (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 estimated glomerular filtration rate (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%, DDD 12%, IC-MPGN 28%). 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/day and eGFR lowering steeper than –5 mL/min/1.73 m 2 /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 biological heterogeneity. Longitudinal eGFR and proteinuria provide powerful prognostic information, and clinically meaningful thresholds (>1 g/day time-averaged proteinuria; eGFR slope steeper than –5 mL/min/1.73 m 2 /year) refine risk stratification. Dynamic biomarkers may serve as surrogate endpoints, underscoring the need for prospective validation with emerging proximal complement therapies.
2026-06-29 | Mechanism-centered target discovery across glomerulonephritis phenotypes: an integrative multi-omics study.
Glomerulonephritis (GN) comprises a heterogeneous group of immune-mediated kidney disorders with substantial biological and clinical diversity. Current treatment still relies largely on broad immunosuppression, underscoring the need for mechanism-informed target discovery across GN phenotypes. We performed a program-guided integrative multi-omics study by combining cis-expression quantitative trait loci and cis-protein quantitative trait loci with GN genome-wide association datasets from UK Biobank, the GWAS Catalog, and FinnGen. Candidate genes were organized into four predefined mechanistic programs: cytokine/TNF signaling, cell-cycle/senescence-repair balance, complement/innate immune activation, and regulated cell-death/redox stress. Six GN-related outcomes were analyzed. Bayesian colocalization, cross-dataset meta-analysis, mouse knockout annotation, drug-repurposing assessment, network pharmacology, and rule-based evidence scoring were used to refine target prioritization. Integrative screening identified 42 transcriptomic and 12 proteomic putative targets, with the strongest enrichment in non-proliferative glomerulonephritis and primary membranoproliferative glomerulonephritis. Bayesian colocalization supported PPP2R1B in non-proliferative glomerulonephritis, SOD1 in IgA nephropathy, and CDK4 in primary membranoproliferative glomerulonephritis. Among 42 transcriptomic gene-outcome pairs taken forward, 11 were supported by cross-dataset meta-analysis. Proteomic meta-analysis supported several cross-dataset signals, including protective associations of ANXA5, GSR, and TNFRSF1B with glomerulonephritis. Across outcomes, complement/innate immunity and cytokine/TNF signaling formed the dominant shared backbone. After separating MHC-region signals for cautious interpretation, 31 non-MHC targets were retained for primary prioritization, with PPP2R1B, CDK4, and SOD1 comprising the top tier. This mechanism-centered integrative multi-omics study delineates shared and phenotype-enriched biological programs across the GN spectrum and identifies a prioritized set of candidate targets for future validation and therapeutic development.
2026-06-05 | Immune complex-mediated membranoproliferative glomerulonephritis following scabies infestation in a child: a rare association.
Scabies, caused by Sarcoptes scabiei var. hominis, is a common parasitic infestation in tropical regions. Although primarily dermatological, it can rarely trigger systemic complications such as immune complex-mediated membranoproliferative glomerulonephritis (MPGN). A 14-year-old boy presented with bilateral pedal edema, facial puffiness, and reddish urine for one week. Examination revealed pruritic papular lesions over the interdigital spaces, and microscopy confirmed Sarcoptes scabiei infestation. Investigations showed nephrotic-range proteinuria (4.9 g/day), microscopic hematuria, and normal complement levels. Kidney biopsy demonstrated immune complex-mediated MPGN with crescent formation. The patient was treated with topical 5% permethrin and oral ivermectin for scabies, followed by corticosteroid pulses and monthly cyclophosphamide. Complete clinical and biochemical remission occurred within six months. This case highlights scabies as a potential trigger for immune complex-mediated glomerulonephritis through chronic antigenic stimulation. Scabies-associated MPGN, though rare, should be recognized as a treatable cause of immune-mediated kidney injury. Early diagnosis and combined anti-parasitic and immunosuppressive therapy can achieve complete remission.
proteins
2024-02-01 | C3G and Ig-MPGN-treatment standard.
Among the broad spectrum of membranoproliferative glomerulonephritis (MPGN), immunofluorescence distinguishes C3 glomerulopathy (C3G), with predominant C3 deposits, and immunoglobulin-associated MPGN (Ig-MPGN), with combined C3 and Ig. However, there are several intersections between C3G and Ig-MPGN. Primary C3G and Ig-MPGN share the same prevalence of low serum C3 levels and of abnormalities of the alternative pathway of complement, and patients who present a bioptic pattern of Ig-MPGN at onset may show a C3G pattern in a subsequent biopsy. There is no specific therapy for primary C3G and Ig-MPGN and prognosis is unfavourable. The only recommended indications are inhibitors of the renin-angiotensin system, lipid-lowering agents and other renoprotective agents. The other drugs used currently, such as corticosteroids and mycophenolate mofetil, are often ineffective. The anti-C5 monoclonal antibody eculizumab has been tested in several patients, with mixed results. One reason for the uncertainty is the extremely variable clinical course, most likely reflecting a heterogeneous pathogenesis. An unsupervised clustering analysis that included histologic, biochemical, genetic and clinical data available at onset in patients with primary C3G and Ig-MPGN identified four clusters characterized by specific pathogenic mechanisms. This approach may facilitate accurate diagnosis and development of targeted therapies. Several trials are ongoing with drugs targeting different molecules of the complement cascade, however it is important to consider which component of the cascade may be the most appropriate for each patient. We review the current standards of treatment and discuss novel developments in the pathophysiology, diagnosis, outcome prediction and management of C3G and Ig-MPGN.
2018-08-22 | Complement regulation and kidney diseases: recent knowledge of the double-edged roles of complement activation in nephrology.
The complement activation system plays important roles to maintain homeostasis in the host and to fight foreign invaders to protect the host. Therefore, the complement system is considered a core part of innate immunity which also cross-talks to acquired immunity. In the history of nephrology, the complement system is familiar to us, because complement protein or fragment deposition, including C3, C4, C1q, and/or C4d, is routinely estimated by immunohistochemistry to diagnose renal pathologies. The relationships between pathological mechanisms and complement activation have been investigated for renal diseases such as post-infectious glomerulonephritis, lupus nephritis, and primary membranoproliferative glomerulonephritis, which are usually accompanied by hypocomplementemia. However, unregulated complement activation in local areas might be associated with progression of various renal injuries even in the normocomplementemic patient. Recently, attention has focused on dysfunction of complement regulation in various diseases including renal diseases such as atypical hemolytic uremic syndrome and C3 glomerulopathy. Some mechanisms associated with complement activation in these diseases were clarified. In addition, lots of anti-complement agents were developed and some of the agents have become clinically available. Now, anti-complement therapies represent a realistic choice of therapeutic approaches for complement-related diseases. Research on roles of complement activation is proceeding into new stages in the field of nephrology and in other fields involving both basic and clinical research. We herein summarize relationships between the complement activation and regulation systems, their physiological effects and roles in maintenance of homeostasis in the host, and how dysregulation of the complement system triggers disease, especially renal disease.
2017-09-05 | Chronic hepatitis C virus (HCV) increases the risk of chronic kidney disease (CKD) while effective HCV treatment decreases the incidence of CKD
We assessed the risk of chronic kidney disease (CKD) in chronic hepatitis C virus (HCV)‐infected patients and the incidence reduction of CKD after receipt of HCV treatment. We also evaluated the risk of membranoproliferative glomerulonephritis (MPGN) and cryoglobulinemia in chronic HCV patients. A retrospective cohort analysis of the Truven Health MarketScan Database (2008‐2015) in the United States was conducted. In a cohort of 56,448 HCV‐infected patients and 169,344 propensity score (1:3)–matched non‐HCV patients, we examined the association of HCV infection with the incidence of CKD. Of 55,818 HCV patients, 6.6 % (n = 3666), 6.3% (n = 3534), and 8.3% (n = 4628) patients received either interferon‐based dual, triple, or all‐oral direct acting antiviral agent therapy, respectively, whereas 79% of patients did not receive any HCV treatment. Cox proportional hazards models were used to compare the risk of developing CKD in HCV patients compared with non‐HCV patients and treated patients compared with untreated HCV patients. In a multivariate time‐varying Cox regression model, HCV‐infected patients had a 27% increased risk of CKD compared with non‐HCV patients (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.18‐1.37). Among HCV patients, individuals who received the minimally effective HCV treatment for dual, triple, or all‐oral therapy had a 30% decreased risk of developing CKD (HR, 0.70; 95% CI, 0.55‐0.88). In addition, HCV‐infected patients experienced a twofold and a nearly 17‐fold higher risk of MPGN (HR, 2.23; 95% CI, 1.84‐2.71) and cryoglobulinemia (HR, 16.91; 95% CI, 12.00‐23.81) respectively, compared with non‐HCV patients. Conclusion: HCV‐infected individuals in the United States are at greater risk of developing CKD, MPGN, and cryoglobulinemia. Minimally effective treatment of HCV infection can prevent the development of CKD, although the association was not significant for all‐oral therapy. (H epatology 2018;67:492‐504).
2014-10-01 | The complement cascade and renal disease.
Serum complement cascade, a part of innate immunity required for host protection against invading pathogens, is also a mediator of various forms of disease and injury. It is activated by classical, lectin, and alternative pathways that lead to activation of C3 component by C3 convertases, release of C3b opsonin, C5 conversion and eventually membrane attack complex formation. The tightly regulated activation process yields also C3a and C5a anaphylatoxins, which target a broad spectrum of immune and non-immune cells. The review discusses the involvement of the complement cascade in kidney disease pathogenesis and injury. The role of the complement pathways in autoantibody-mediated forms of glomerulonephritis (lupus nephritis, anti-glomerular basement membrane disease, anti-neutrophil cytoplasmic autoantibody-induced or membranoproliferative glomerulonephritis, membranous nephropathy), C3 glomerulopathy, atypical forms of hemolytic uremic syndrome, ischemic-reperfusion injury of transplanted kidney, and antibody-mediated renal allograft rejection are discussed. The disturbances in complement activation and regulation with underlying genetics are presented and related to observed pathology. Also promising strategies targeting the complement system in complement-related disorders are mentioned.
2012-08-06 | A novel, dual role of CCN3 in experimental glomerulonephritis: pro-angiogenic and antimesangioproliferative effects.
In contrast to factors that promote mesangial cell proliferation, little is known about their endogenous inhibitors. During experimental mesangioproliferative nephritis, expression of the glomerular CCN3 (nephroblastoma overexpressed gene [NOV]) gene is reduced before the proliferative phase and increased in glomeruli and serum when mesangial cell proliferation subsides. To further elucidate its role in mesangioproliferative glomerulonephritis, CCN3 systemically was overexpressed by muscle electroporation in healthy or nephritic rats. This increased CCN3 serum concentrations more than threefold for up to 56 days. At day 5 after disease induction, CCN3-transfected rats showed an increase in glomerular endothelial area and in mRNA levels of the pro-angiogenic factors vascular endothelial growth factor and PDGF-C. At day 7, CCN3 overexpression decreased mesangial cell proliferation, including expression of α-smooth muscle actin and matrix accumulation of fibronectin and type IV collagen. In progressive nephritis (day 56), overexpression of CCN3 resulted in decreased albuminuria, glomerulosclerosis, and reduced cortical collagen type I accumulation. In healthy rat kidneys, overexpression of CCN3 induced no morphologic changes but regulated glomerular gene transcripts (reduced transcription of PDGF-B, PDGF-D, PDGF-receptor-β, and fibronectin, and increased PDGF-receptor-α and PDGF-C mRNA). These data identify a dual role for CCN3 in experimental glomerulonephritis with pro-angiogenic and antimesangioproliferative effects. Manipulation of CCN3 may represent a novel approach to help repair glomerular endothelial damage and mesangioproliferative changes.
antibodies
2026-06-22 | Natural History of C3 Glomerulopathy and Immune Complex-Associated Membranoproliferative Glomerulonephritis in Children.
C3 glomerulopathy (C3G) and immune complex-associated membranoproliferative glomerulonephritis (IC-MPGN) are rare complement-mediated kidney diseases with a high risk of progression to kidney failure. Little is known about the natural history of these diseases in children, limiting our understanding of risk factors for progressive kidney disease. Using a computable phenotype algorithm, a pediatric cohort with C3G or IC-MPGN was identified at seven institutions in PEDSnet, a national network of pediatric health systems which aggregate electronic health record data and collaborate on pragmatic research studies. Discrete data elements were captured from electronic health records and additional clinical and histopathologic data were extracted by standardized chart review by pediatric nephrologists. Biopsy diagnosis was classified as C3G or IC-MPGN by applying an algorithm based on immunofluorescence and electron microscopy and supplemented with manual chart review. Kaplan-Meier survival curves were utilized to compare the risk of reaching a composite kidney outcome of 50% reduction in estimated glomerular filtration rate (eGFR), initiation of maintenance dialysis, or kidney transplantation. Of 204 patients with MPGN identified by the computable phenotype algorithm and chart review, 159 could be further classified as C3G or IC-MPGN based on available biopsy data. There were no significant differences in baseline serum albumin, C3 level, urine protein/creatinine ratio, or eGFR between C3G or IC-MPGN. Patients with C3G and IC-MPGN had similar rates of progression to the composite kidney outcome, and a low serum C3 level at baseline was associated with this composite outcome. Using large-scale, real-world multi-institutional data, we investigated the natural history of a large contemporary cohort of children with MPGN. As patients classified as having C3G compared to IC-MPGN had similar baseline clinical characteristics and rates of progressive disease despite untargeted treatment approaches, the availability of newer complement-targeted agents hold the promise of benefit to this population.
2026-02-20 | A nephritic puzzle: C3-dominant glomerulonephritis as a sentinel of hidden autoinflammatory disease.
Membranoproliferative glomerulonephritis (MPGN) is among the most challenging glomerulonephritides to diagnose and manage, given its clinico-immunopathologic heterogeneity. Although recent advances have introduced new therapies for complement-mediated and immune-complex MPGN, a substantial subset of cases remains poorly understood and lacks effective treatment. We report a pediatric case of biopsy-confirmed C3-dominant MPGN without evidence of complement dysregulation, with disease flares triggered by febrile episodes. Genetic testing identified underlying hyper-IgD syndrome (HIDS), a rare autoinflammatory disorder characterized by recurrent fevers and immune dysregulation. The patient's MPGN was refractory to conventional immunosuppressive therapy but achieved remission with IL-1β blockade that targets HIDS. This case highlights the importance of considering alternative etiologies-including autoinflammatory diseases-in patients with MPGN when complement dysregulation is not evident.
2025-12-03 | Trial of Pegcetacoplan in C3 Glomerulopathy and Immune-Complex MPGN.
C3 glomerulopathy and primary immune-complex membranoproliferative glomerulonephritis (MPGN) generally result in glomerular C3 deposition and irreversible kidney damage. The efficacy and safety of pegcetacoplan, a C3 and C3b inhibitor, in persons with C3 glomerulopathy or primary immune-complex MPGN are unclear. We conducted a phase 3, double-blind, placebo-controlled trial involving adolescents and adults with C3 glomerulopathy or primary immune-complex MPGN, including those with native kidney disease and those with disease recurrence after transplantation. Patients were randomly assigned in a 1:1 ratio to receive pegcetacoplan or placebo. The primary end point was the log-transformed ratio of the urinary protein-to-creatinine ratio at week 26 as compared with baseline. A total of 124 patients underwent randomization. The change in proteinuria (as measured by the log-transformed ratio to baseline in the urinary protein-to-creatinine ratio) was significantly greater with pegcetacoplan than with placebo (geometric mean of the urinary protein-to-creatinine ratio, -67.2% [95% confidence interval {CI}, -74.9 to -57.2] vs. 2.9% [95% CI, -8.6 to 15.9]). The difference represents a relative reduction of 68.1% (95% CI, 57.3 to 76.2) as compared with placebo. In hierarchical testing of five secondary end points, significantly higher percentages of patients in the pegcetacoplan group than in the placebo group met the composite renal end-point criteria (stabilization of estimated glomerular filtration rate [eGFR] and ≥50% reduction in urinary protein-to-creatinine ratio) (49% vs. 3%) and had at least a 50% reduction in the protein-to-creatinine ratio (60% vs. 5%). Among 69 patients with evaluable kidney-biopsy samples, the change in the activity score of the C3 glomerulopathy histologic index did not differ significantly between the two groups; subsequent end points (decrease in C3 staining and change in eGFR) were not formally tested. Pegcetacoplan was not associated with more adverse events than placebo. No serious infections from encapsulated bacteria occurred; 1 patient receiving pegcetacoplan died from coronavirus disease 2019 pneumonia. No allograft rejection or loss occurred. Pegcetacoplan resulted in a significantly greater reduction in proteinuria than placebo among patients with C3 glomerulopathy or primary immune-complex MPGN. (Funded by Apellis Pharmaceuticals and Sobi [Swedish Orphan Biovitrum]; VALIANT ClinicalTrials.gov number, NCT05067127.).
2025-10-12 | Hierarchical clustering uncovered disease patterns and further untangled complexities in immune complex-mediated idiopathic MPGN and C3 glomerulopathy.
Membranoproliferative glomerulonephritis (MPGN) is currently stratified into complement C3 glomerulopathy (C3G) and immune complex-mediated MPGN (IC-MPGN). However, classification is subject to continued debate. Here, we applied hierarchical clustering to a much larger cohort of patients with C3G/IC-MPGN (295 individuals), extensively characterized for genetic and autoimmune complement abnormalities, with the goal of unraveling specific disease patterns. We also designed a user-friendly web application that with input of data at diagnosis could make cluster classification clinically applicable. Five clusters with unique phenotypic and complement profiles were identified. Cluster 1 and 2 patients showed systemic complement activation until C5. Consistently, C5 nephritic factor and anti-factor B antibodies were prevalent in these clusters. Cluster 2 was distinguished from cluster 1 for classical pathway activation markers in biopsy. Cluster 3 showed C3-restricted systemic complement activation associated with the prevalence of C3 nephritic factor. Cluster 4 and 5 patients shared a normal complement profile and intense glomerular C3 staining, consistent with solid-phase complement activation, but cluster 5 distinguished for the higher prevalence of genetic abnormalities. Cluster 4 patients had the highest incidence of kidney failure during follow-up, while cluster 1 had the best kidney prognosis. However, clusters 1 and 2 showed a high risk of post-transplant recurrence. Through our web application, we could visually compare the predicted profile of new patients with those of patients included in clustering analysis and assign these patients to different clusters. The cluster-based classification allows etiologic diagnosis of C3G/IC-MPGN and had better prognostic value than current approaches. Our proposed strategy may possibly guide anti-complement treatment.
2025-10-01 | #3363 Diagnostic gaps in C3G and ic-MPGN: findings of the CompCure study cohort
Abstract Background and Aims C3 glomerulopathy (C3G) and immune complex-mediated membranoproliferative glomerulonephritis (ic-MPGN) are chronic kidney disorders characterized by abnormal activation of the alternative complement pathway. The etiology of the conditions is heterogeneous and variably involves C3 activating auto-antibodies, alterations in complement regulating genes and activation of the terminal complement pathway. Classification by diagnostic biomarker panels has been proposed to improve outcome prediction. While currently available non-specific immunosuppressive and antiproteinuric therapies yield highly variable long-term disease outcomes, new treatments targeting individual components of the complement system are in development. These emerging novel therapeutic options increase the need for standardized, comprehensive diagnostic evaluation of C3G/ic-MPGN to empower rational, personalized treatment approaches. The European Rare Kidney Disease Reference Network (ERKNet) and the CompCure Association for complement-mediated diseases have recently established a large prospective registry study following adults and children with C3G/ic-MPGN. The CompCure project aims to explore the association of diagnostic biomarkers with treatment responsiveness and disease outcomes. Here, we analyzed the completeness of available complement diagnostic features and the detection rate of abnormalities in the study cohort. Method A total of 236 patients were analyzed, including 157 with C3G (141 C3GN, 16 DDD) and 70 with ic-MPGN, registered across 36 European nephrology referral centers (30 pediatric, 11 adult). Disease onset was during childhood in 70% of the patients. 77% of patients were enrolled within 6 months of diagnosis. The diagnosis was established by kidney biopsy with immunofluorescence and electron microscopy in all cases. Results At time of diagnosis, global CH50 and AP50 complement tests were conducted in 26% and 15% of cases, respectively. While serum C3 was tested in 71% and C4 in 69% of patients, other complement proteins were rarely assessed: Factor H in 17%, C5 in 3%, and Properdin in 2%. The membrane attack complex (sC5b-9) was measured in 32%, and Bb in 4%. Among autoantibodies, C3Nef was tested in 33%, anti-FH in 31%, anti-FB in 9%, anti-C3b in 11%, and C5Nef in 5% of patients. Genetic testing was performed in 56% of C3GN, 75% of DDD, and 15% of ic-MPGN patients. The assessment of core diagnostic features increased with time during the observation period: Conclusion The diagnostic evaluation of patients with C3G/ic-MPGN in European referral centers primarily relies on histopathological findings and serum C3 levels. Essential tests such as sC5b-9, C3Nef and other autoantibodies as well as complement gene screening are still performed in a minority of patients. Reasons for the incomplete diagnostic assessment may include the low number of specialized complement diagnostic laboratories in Europe, a lack of standardized diagnostic panels, high cost and long processing times. This gap in diagnostic practices hampers accurate disease classification and patient stratification for personalized treatment protocols. The CompCure cohort study will support participating sites to obtain standardized diagnostics in newly diagnosed patients with C3G/ic-MPGN.
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Drug Discovery Landscape
2 orphan drug designations for Primary membranoproliferative glomerulonephritis.
2 orphan drug designations for Primary membranoproliferative glomerulonephritis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Human IgG1 minibody against Complement C5 [MUBODINA] | antibodies | EMA | 2011-10-27 | — | Adienne S.r.l. |
recombinant human minibody against complement component C5 | antibodies | FDA | 2009-02-04 | — | ADIENNE S.A. |
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