Mycophenolate Mofetil in C3 Glomerulopathy and Pathogenic Drivers of the Disease
Authors: Caravaca-Fontán Fernando , Díaz-Encarnación Montserrat M. , Lucientes Laura , Cavero Teresa , Cabello Virginia , Ariceta Gema , Quintana Luis F. , Marco Helena , Barros Xoana , Ramos Natalia , Rodríguez-Mendiola Nuria , Cruz Sonia , Fernández-Juárez Gema , Rodríguez Adela , Pérez de José Ana , Rabasco Cristina , Rodado Raquel , Fernández Loreto , Pérez Gómez Vanessa , Ávila Ana I. , Bravo Luis , Lumbreras Javier , Allende Natalia , Sanchez de la Nieta Maria Dolores , Rodríguez Eva , Olea Teresa , Melgosa Marta , Huerta Ana , Miquel Rosa , Mon Carmen , Fraga Gloria , de Lorenzo Alberto , Draibe Juliana , Cano-Megías Marta , González Fayna , Shabaka Amir , López-Rubio Maria Esperanza , Fenollosa María Ángeles , Martín-Penagos Luis , Da Silva Iara , Alonso Titos Juana , Rodríguez de Córdoba Santiago , Goicoechea de Jorge Elena , Praga Manuel ,   on behalf of the Spanish Group for the Study of Glomerular Diseases GLOSEN
Published: August 2020

Background and objectives
C3 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).

Results
The 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.

Conclusions
The beneficial response to corticosteroids plus MMF treatment in C3 glomerulopathy appears independent of the pathogenic drivers analyzed in this study.