C5 Convertase Blockade in Membranoproliferative Glomerulonephritis: A Single-Arm Clinical Trial

Gennarini, Alessia; Remuzzi, Giuseppe; Ruggenenti, Piero; Mondo, Elena; Rota, Stefano; Portalupi, Valentina; Pasini, Andrea; Monitini, G.; Monti, Elena; Rigotti, Angelo; Giovanni, F. De; Giacon, Bruno; Lerchner, R.; Passler, Werner; Santoro, Domenico; Visconti, Luca; Pisani, Antonio; Riccio, Eleonora; Pasi, Alessandra; Dugo, Mauro; Tuono, C.; Emma, Francesco; Vivarelli, Marina; Murer, Luisa; Benetti, Elisa; Coppo, Rosanna; Amore, Alessandro; Gambaro, Giovanni; Passalacqua, S.; Ruggiero, Barbara; Daina, Erica; Bresin, Elena; Gamba, Sara; Prandini, Silvia; Lecchi, V.; Cugini, Daniela; Gherardi, Giulia; Rubis, Nadia; Diadei, Olimpia; Villa, Alessandro; Villa, Davide; Boccardo, Paola; Peracchi, S.; Martinetti, Davide; Perna, Annalisa; Peraro, Francesco; Giuliano, Giovanni; Gaspari, Flavio; Carrara, Fabiola; Ferrari, Silvia; Stucchi, Nadia; Cannatà, Antonio; Noris, Marina; Bettoni, Serena; Alberti, Marta; Cuccarolo, Paola; Carrara, Camillo; Rizzo, Paola; Marchetti, Gianfranco; Sonzogni, Aurelio

doi:10.1053/j.ajkd.2018.12.046

Cited by 48 publications

(38 citation statements)

References 37 publications

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“…It has been evaluated in a small retrospective series 6 and more recently in a prospective, nonrandomized, off-on-off-on, open label study. 9 In both reports, eculizumab use was not associated with a uniformly beneficial effect on the history of C3G or Ig-MPGN, in r e v i e w sharp contrast to what has been previously documented in patients with aHUS. 10 In the first retrospective study 6 that included 26 pediatric and adult patients with C3G, the effect of eculizumab was clear and probably cost-effective only in a minority (roughly a quarter) of patients, mostly with rapidly progressive disease.…”

Section: The Uncertain Role Of Monoclonal Gammopathy and C3gmentioning

confidence: 69%

Practical management of C3 glomerulopathy and Ig-mediated MPGN: facts and uncertainties

Fakhouri

Quintrec

Frémeaux‐Bacchi

2020

Kidney International

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Section: The Uncertain Role Of Monoclonal Gammopathy and C3gmentioning

confidence: 69%

Practical management of C3 glomerulopathy and Ig-mediated MPGN: facts and uncertainties

Fakhouri

Quintrec

Frémeaux‐Bacchi

2020

Kidney International

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“…There is a scarcity of data about treatment strategies in C3 glomerulopathy. Eculizumab, a humanized mAb against complement protein C5, has been tested in C3 glomerulopathy with limited results (14)(15)(16), suggesting a particular benefit among patients with rapidly progressive presentations.…”

Section: Introductionmentioning

confidence: 99%

Mycophenolate Mofetil in C3 Glomerulopathy and Pathogenic Drivers of the Disease

Caravaca-Fontán

Díaz-Encarnación

Lucientes

et al. 2020

CJASN

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Background and objectivesC3 glomerulopathy is a complement-mediated disease arising from abnormalities in complement genes and/or antibodies against complement components. Previous studies showed that treatment with corticosteroids plus mycophenolate mofetil (MMF) was associated with improved outcomes, although the genetic profile of these patients was not systematically analyzed. This study aims to analyze the main determinants of disease progression and response to this therapeutic regimen.Design, setting, participants, & measurements We conducted a retrospective, multicenter, observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases. Patients diagnosed with C3 glomerulopathy (n=81) or dense deposit disease (n=16) between January 1995 and March 2018 were enrolled. Multivariable and propensity score matching analyses were used to evaluate the association of clinical and genetic factors with response to treatment with corticosteroids and MMF as measured by proportion of patients with disease remission and kidney survival (status free of kidney failure).ResultsThe study group comprised 97 patients (84% C3 glomerulopathy, 16% dense deposit disease). Forty-two patients were treated with corticosteroids plus MMF, and this treatment was associated with a higher rate of remission and lower probability of kidney failure (79% and 14%, respectively) compared with patients treated with other immunosuppressives (24% and 59%, respectively), or ecluzimab (33% and 67%, respectively), or conservative management (18% and 65%, respectively). The therapeutic superiority of corticosteroids plus MMF was observed both in patients with complement abnormalities and with autoantibodies. However, patients with pathogenic variants in complement genes only achieved partial remission, whereas complete remissions were common among patients with autoantibody-mediated forms. The main determinant of no remission was baseline proteinuria. Relapses occurred after treatment discontinuation in 33% of the patients who had achieved remission with corticosteroids plus MMF, and a longer treatment length of MMF was associated with a lower risk of relapse.ConclusionsThe beneficial response to corticosteroids plus MMF treatment in C3 glomerulopathy appears independent of the pathogenic drivers analyzed in this study.

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“…Another recent open-label clinical trial with an off-onoff-on design evaluated the effect of eculizumab on proteinuria in patients with immune-complex-mediated MPGN and C3G, with baseline plasma C5b-9 levels >1,000 ng/mL and proteinuria >3.5 g/24 h [47]. Only 3 of 10 study patients achieved a significant reduction in 24-h proteinuria, thereby suggesting that other upstream, probably C3-dependent pathways could play a role in the underlying pathogenesis [47].…”

Section: Anticomplement Therapymentioning

confidence: 99%

Update on C3 Glomerulopathy: A Complement-Mediated Disease

Caravaca-Fontán

Lucientes

Cavero

et al. 2020

Nephron

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C3 glomerulopathy (C3G) is a clinicopathologic entity secondary to dysregulation of the alternative complement pathway in plasma and the glomerular microenvironment. The current consensus definition of C3G relies on immunofluorescence staining criteria. However, due to its high clinical variability, these criteria may not be accurate enough in some clinical scenarios. Thus, a new pathogenic classification based on a cluster analysis of clinical, histologic, and genetic data has recently been proposed, which could also help identify patients at higher risk of progression. Several pathogenic abnormalities in complement genes have been described, and the role of autoantibodies in the disease is increasingly recognized, but still the genotype-phenotype correlations in C3G are poorly understood. C3G may be diagnosed in both children and adults. The spectrum of clinical manifestations is wide, although one of the most common clinical presentations is proteinuria with relatively preserved kidney function. In order to standardize the evaluation of kidney biopsies from these patients, a histopathologic index was recently proposed, including both parameters of activity and chronicity. However, this index has not yet been val-idated in independent cohorts. Currently, no targeted therapies are available in clinical settings for the treatment of C3G, although several new molecules are under investigation. Treatment with corticosteroids plus mycophenolate mofetil has been shown to be associated with improved renal outcomes, as compared to other immunosuppressive regimens. Yet, the main determinants of treatment response with this regimen and the influence of the underlying pathogenic drivers have not been extensively studied. The therapeutic response to eculizumab, an anti-C5 monoclonal antibody, has been shown to be highly heterogeneous. Thus, its current clinical indication in C3G is restricted to rapidly progressive forms of the disease. To summarize, in recent years, several important advances have taken place in the understanding of C3G, but still further studies are warranted to elucidate the best therapeutic strategies that could improve prognosis of this entity.

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C5 Convertase Blockade in Membranoproliferative Glomerulonephritis: A Single-Arm Clinical Trial

Cited by 48 publications

References 37 publications

Practical management of C3 glomerulopathy and Ig-mediated MPGN: facts and uncertainties

Practical management of C3 glomerulopathy and Ig-mediated MPGN: facts and uncertainties

Mycophenolate Mofetil in C3 Glomerulopathy and Pathogenic Drivers of the Disease

Update on C3 Glomerulopathy: A Complement-Mediated Disease

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