一次性膜性増殖性糸球体腎炎

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 m2/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 m2/year) refine risk stratification. Dynamic biomarkers may serve as surrogate endpoints, underscoring the need for prospective validation with emerging proximal complement therapies.

BACKGROUND: C3 glomerulopathy (C3G) is a rare kidney disease caused by uncontrolled activation of the complement alternative pathway (AP), frequently driven by nephritic factors (NeFs) that stabilize the AP C3 and C5 convertases. NeFs are detected in up to 80% of patients and exhibit heterogeneous stabilizing activity, contributing to variable degrees of complement dysregulation. Current complement-targeted therapies reduce complement activation but may compromise immune surveillance by blocking key components of the pathway. Supplementation with the physiological AP regulator factor H (FH) represents an alternative strategy aimed at restoring complement homeostasis while preserving essential immune functions. CPV-104 is a fully functional recombinant human FH produced in moss, with optimized glycosylation and improved pharmacokinetics, offering a promising therapeutic approach for C3G. OBJECTIVES AND METHODS: We evaluated the ability of CPV-104 to antagonize NeF-mediated stabilization of the AP C3 convertase (C3bBb) in eight C3G patients enrolled in the Italian MPGN/C3G Registry. Patients were classified as C3NeF+ or C5NeF+ based on properdin dependence in convertase stabilization assays. NeF activity was analyzed using solid-phase assays in which C3bBb decay and formation were assessed in the presence of CPV-104 or serum-derived FH (sd-FH). The impact of CPV-104 ex vivo was tested in fluid-phase assays using patient sera, with Ba (convertase formation) and C3a (convertase activity) measured by ELISA. RESULTS: CPV-104 accelerated decay of NeF-stabilized C3bBb with efficacy comparable to sd-FH. Convertases stabilized by six of eight NeFs were fully dissociated by CPV-104, while two highly potent C3NeFs were partially antagonized. When added during convertase assembly, CPV-104 significantly reduced C3bBb formation in all patients and showed a stronger inhibitory effect than sd-FH. In fluid-phase assays, using patient sera, CPV-104 markedly decreased Ba and C3a generation, with mean inhibition of 68.9% and 51.8%, respectively, and consistently outperformed sd-FH across patient samples. CONCLUSIONS: CPV-104 effectively limits both stabilization and formation of AP C3 convertases in NeF-positive C3G, demonstrating superior functional activity compared with sd-FH. By restoring physiological AP regulation rather than broadly inhibiting complement activation, CPV-104 represents a promising and potentially safer therapeutic strategy for NeF-driven C3G and warrants further clinical investigation.

Monoclonal gammopathies of renal significance constitute a heterogeneous spectrum of nephropathies characterised by renal deposition of monoclonal immunoglobulins or their fragments, produced by clonal proliferation of B lymphocytes or plasma cells, in the absence of diagnostic criteria for symptomatic multiple myeloma or overt lymphoma. In recent years, the growing recognition of these nosological entities has highlighted how early diagnosis and the implementation of clone-directed therapeutic strategies can significantly alter the natural history of the disease and improve long-term renal outcomes. Within this complex classification, proliferative glomerulonephritis with monoclonal immunoglobulin deposits is an exceptionally rare histological diagnosis, typically burdened by an unfavourable renal prognosis and a high risk of progression to end-stage renal disease. The peculiarity of this entity lies in the granular non organised deposition of monoclonal immunoglobulins at the glomerular level, which triggers an endocapillary and/or mesangial proliferative process with consequent impairment of filtration function. We present the clinical case of a 65-year-old male patient who developed overt nephrotic syndrome associated with rapidly progressive renal failure. Renal biopsy revealed PGNMID in the context of MGRS underlying marginal zone B-cell lymphoma. The patient underwent combination treatment with high-dose corticosteroids and rituximab, achieving an excellent clinical response characterised by complete remission of the nephrotic syndrome and normalisation of renal function. This case highlights the importance of a multidisciplinary diagnostic approach in MGRS and the potential benefit of clone-targeted therapies in the management of PGNMID, even in the presence of acute deterioration of renal function.

Background. The complement system plays a critical role in the pathogenesis of several kidney diseases. Dysregulation of complement activation, particularly of the alternative pathway, leads to kidney injury via thrombotic microangiopathy, immune complex deposition, and direct podocyte damage. Summary. Complement system inhibitors represent a paradigm shift in nephrology therapeutics, offering targeted treatment for diseases previously associated with poor outcomes. This review comprehensively examines the present landscape of complement inhibition in kidney disease, including established therapies and emerging agents. Terminal complement inhibitors (eculizumab and ravulizumab) have revolutionized the treatment of atypical haemolytic uremic syndrome, demonstrating remarkable improvements in renal outcomes and survival. Proximal pathway inhibitors targeting Factor B (Iptacopan) and C3 (pegcetacoplan) show promise in C3 glomerulopathy and IgA nephropathy, with recent phase 3 trials demonstrating significant proteinuria reduction. Additional applications include immune complex membranoproliferative glomerulonephritis and ANCA-associated vasculitis, in which complement activation contributes to disease pathogenesis. However, these agents present unique challenges, including infection risk, particularly meningococcal disease, cost considerations, and uncertainty regarding optimal treatment duration.

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.