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:
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.
2026-06-22 | 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.
2026-08-09 | 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.
2026-06-22 | 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.
Access all drug discovery papers and probability of success in trials forecasts:
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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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