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Primary membranoproliferative glomerulonephritis: natural history, pathogenesis, and treatment
Edward J Filippone1, John L Farber2
1Division of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States.
Abstract:
Primary membranoproliferative glomerulonephritis (MPGN) is an ultrarare disease characterized by immunofluorescence microscopy as either immune-complex mediated (IC-MPGN) or C3 glomerulopathy (C3), the latter subdivided by electron microscopy to C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). Both IC-MPGN and C3G typically have obvious C3 staining differentiating them from other causes of MPGN histology. Secondary causes must be excluded, including infections, autoimmune disease, and neoplasia. Clinical presentations are variable, including urinary sediment abnormalities, nephrotic syndrome, or a rapidly progressive course. The prognosis is unfavorable with about 50% reaching kidney failure by 10 years. Recurrence following transplantation is frequent, and allograft survival is shortened. The pathogenesis involves dysregulation of the alternate pathway (AP) of complement. Possibly 20% of patients harbor pathogenic mutations in AP proteins or their regulators, and up to 80% have autoantibodies impairing normal regulation. Paraproteins are found in 20 - 40% of otherwise primary MPGN, either directly detectable on biopsy (IC-MPGN) or as dysregulators of the AP. Therapy of MPGN begins with supportive care as for all glomerulopathies. Paraproteins require clone-directed therapy. When immunosuppression is considered, complement inhibition should be first line. Two agents are now FDA approved for C3G, the oral Factor B inhibitor iptacopan and the subcutaneous C3-inhibitor pegcetacoplan, the latter also approved for IC-MPGN. If complement inhibition is unavailable, MMF/steroids may be considered. Following transplantation, protocol biopsies are needed to detect early recurrence with the intent of complement inhibition.
Insights
Primary membranoproliferative glomerulonephritis (MPGN) is a rare kidney disease often involving complement dysregulation. Complement inhibition therapies, like iptacopan and pegcetacoplan, are now key treatments for MPGN, improving patient outcomes.
Area of Science:
- Nephrology
- Immunology
- Complement System
Background:
- Primary membranoproliferative glomerulonephritis (MPGN) is an ultrarare kidney disease classified as immune-complex mediated (IC-MPGN) or C3 glomerulopathy (C3), including C3 glomerulonephritis (C3GN) and dense deposit disease (DDD).
- Distinguishing MPGN subtypes relies on immunofluorescence and electron microscopy, with C3 staining being a common feature differentiating them from other MPGN causes.
- MPGN presents variably, from urinary abnormalities to nephrotic syndrome or rapid progression, carrying a poor prognosis with high rates of kidney failure and post-transplant recurrence.
Purpose of the Study:
- To review the classification, pathogenesis, clinical presentation, and therapeutic strategies for primary MPGN.
- To highlight the central role of complement alternate pathway dysregulation in MPGN pathogenesis.
- To discuss the emerging therapeutic landscape, focusing on complement inhibitors.
Main Methods:
- Literature review of primary MPGN, focusing on classification, diagnostic criteria, and pathogenesis.
- Analysis of clinical presentations, prognostic factors, and outcomes, including post-transplant recurrence.
- Evaluation of current and emerging therapeutic approaches, including supportive care, immunosuppression, and targeted complement inhibition.
Main Results:
- Primary MPGN pathogenesis is linked to complement alternate pathway dysregulation, driven by mutations or autoantibodies in up to 80% of cases.
- Paraproteins are identified in 20-40% of MPGN patients, potentially contributing to complement dysregulation.
- Two complement inhibitors, iptacopan (Factor B inhibitor) and pegcetacoplan (C3 inhibitor), are FDA-approved for C3G and IC-MPGN, respectively.
Conclusions:
- Primary MPGN is a serious condition with poor prognosis, often involving complement system dysregulation.
- Complement inhibition therapies represent a significant advancement in MPGN treatment, offering targeted approaches for C3G and IC-MPGN.
- Management requires exclusion of secondary causes, supportive care, and consideration of complement inhibitors as first-line therapy, with vigilant monitoring post-transplantation for recurrence.
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