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.

Introduction The association between a change in proteinuria over time and its impact in kidney prognosis has not been analyzed in C3 glomerulopathy. This study aims to investigate the association between the longitudinal change in proteinuria and the risk of kidney failure. Methods Retrospective, multicenter observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases (GLOSEN). Patients diagnosed with C3 glomerulopathy between 1995 and 2020 were enrolled. A joint modeling of linear mixed-effects models was applied to assess the underlying trajectory of a repeatedly measured proteinuria, and a Cox model to evaluate the association of this trajectory with the risk of kidney failure. Results The study group consisted of 85 patients, 70 C3 glomerulonephritis and 15 dense deposit disease, with a median age of 26 years (range 13–41). During a median follow-up of 42 months, 25 patients reached kidney failure. The longitudinal change in proteinuria showed a strong association with the risk of this outcome, with a doubling of proteinuria levels resulting in a 2.5-fold increase of the risk. A second model showed that a ≥ 50% proteinuria reduction over time was significantly associated with a lower risk of kidney failure (HR: 0.79; 95% CI : 0.56–0.97; p < 0.001). This association was also found when the ≥50% proteinuria reduction was observed within the first 6 and 12 months of follow-up. Conclusion The longitudinal change in proteinuria is strongly associated with the risk of kidney failure. The change in proteinuria over time can provide clinicians a dynamic prediction of kidney outcomes.

Background C3 glomerulopathy is a rare and heterogeneous complement-driven disease. It is often challenging to accurately predict in clinical practice the individual kidney prognosis at baseline. We herein sought to develop and validate a prognostic nomogram to predict the long-term kidney survival. Methods Retrospective, multicenter observational cohort study in 35 nephrology departments belonging to the GLOSEN group. The dataset was randomly divided into training group (n = 87) and validation group (n = 28). The least absolute shrinkage and selection operator (LASSO) regression was used to screen the main predictors of kidney outcome, and used to build the nomogram. Accuracy of the nomogram was assessed by discrimination and risk calibration, in the training and validation sets. Results The study group comprised 115 patients, of whom 46 patients (40%) reached kidney failure in a median follow-up of 49 months (range 24–112). No significant differences were observed in baseline estimated glomerular filtration rate (eGFR), proteinuria or total chronicity score of kidney biopsy, between patients in the training versus those in the validation set. The selected variables by LASSO were eGFR, proteinuria and total chronicity score. Based on Cox model a nomogram was developed for the prediction of kidney survival at 1-, 2-, 5- and 10-years from diagnosis. The C-index of the nomogram was 0.860 (95% confidence interval 0.834–0.887), and calibration plots showed optimal agreement between predicted and observed outcomes. Conclusions We constructed and validated a practical nomogram with good discrimination and calibration, to predict the risk of kidney failure in C3G patients at 1-, 2-, 5- and 10-years.

Introduction C3 glomerulopathy associated with monoclonal gammopathy (C3G-MIg) is a rare entity. Herein, we analyzed the clinical and histologic features of a cohort of C3G-MIg patients. Methods Retrospective, multicenter, observational study. Patients diagnosed with C3G-MIg between 1995–2021 were enrolled. All had genetic studies of the alternative complement pathway. The degree of disease activity and chronicity was analyzed using the C3G histologic index. Descriptive statistics and propensity-score matching (PSM) analysis were used to evaluate the main outcome of the study (kidney failure [KF]). Results The study group included 23 patients: median age 63 years (IQR 48–70), 57% males. IgG kappa was the most frequent MIg (65%). The diagnosis of C3G-MIg was made in transplanted kidneys in 7 patients (30%). Five (22%) had C3 nephritic factor and 5 (22%) anti-factor H antibodies. One patient carried a pathogenic variant in CFH gene. During a follow-up of 40 months (IQR 14–69), 9 patients (39%) reached KF, and these patients had a significant higher total chronicity score in kidney biopsy. Patients who received clone-targeted therapy had a significant higher survival compared to other management. Those who achieved hematological response had a significant higher kidney survival. Outcome was remarkably poor in kidney transplant recipients, 5 of them (71%) reaching KF. By PSM (adjusting for age, kidney function, proteinuria and chronicity score), no significant differences were observed in kidney survival between C3G patients with/without MIg. Conclusions The C3G histologic index can be used in patients with C3G-MIg to predict kidney prognosis, with higher chronicity scores being associated with worse outcomes. Clone-targeted therapies and the development of hematological response, are associated with better kidney prognosis.

on behalf of the Spanish Group for the Study of Glomerular Diseases (GLOSEN) Key Points c Kidney survival in C3 glomerulopathy is significantly higher in patients with a disease chronicity score ,4 and proteinuria ,3.5 g/d, regardless of baseline eGFR. c A faster eGFR decline in C3 glomerulopathy is associated with higher probability of kidney failure. c Patients with glomerulopathy with a progressive reduction in proteinuria over time did not reach kidney failure.