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.

Key Points: Fifty-five percent of patients achieve long-term remission after rituximab treatment. This is influenced by maintenance therapy with rituximab. A substantial reduction of annualized relapse rate and concomitant immunosuppression was observed after rituximab treatment. Background: Long-term outcomes of rituximab-treated adult patients with podocytopathies (either minimal change disease or FSGS) are largely unknown. Methods: A retrospective study at 30 nephrology departments from 15 countries worldwide included rituximab-treated adults with primary podocytopathies and a minimum clinical follow-up of 36 months. The primary outcome was relapse-free survival at 36 months. Results: One hundred eighty-three adult patients (n=64 with FSGS and n=119 with minimal change disease) with difficult-to-treat nephrotic syndrome (68% steroid-dependent/frequently relapsing, 22% steroid-resistant, 85% previously treated with two or more lines of immunosuppressive therapy) were treated with rituximab as part of a remission induction regimen. Complete or partial remission at 6 months after rituximab treatment was achieved in 82%. Eighty-three of 151 (55%) initial responders achieved long-term relapse-free survival over 3 years. Maintenance therapy with rituximab was associated with a better relapse-free survival (hazard ratio, 2.05; 95% confidence interval [CI], 1.07 to 3.91), irrespective of the dosing regimen. At 36 months, 61% of initial responders receiving maintenance therapy with rituximab achieved long-term relapse-free survival and withdrawal of all concomitant immunosuppressive medication compared with 36% of patients without maintenance treatment (odds ratio, 2.69; 95% CI, 1.27 to 5.73). Relapses per year were reduced from an annual relapse rate of 1.0 (95% CI, 1.0 to 1.7) before to 0.17 (95% CI, 0.00 to 0.24) relapses per year after rituximab initiation. Over the 36 months of follow-up, a stable course of eGFR was observed in those who initially responded with either complete or partial remission, whereas nonresponders experienced a reduction in eGFR reaching −11 (95% CI, −18 to −8) ml/min per 1.73 m². Conclusions: Rituximab facilitated achievement of initial and long-term response in a majority of adult patients with difficult-to-treat podocytopathies. Maintenance treatment with rituximab was further associated with long-term relapse-free survival over 3 years. Nonresponse to initial rituximab treatment was associated with poor kidney prognosis.

Kidney transplants from living donors (LD) have better outcome than those from deceased donors (DD). Different factors have been suggested to justify the different outcome. In this study, we analyzed the infiltration and phenotype of monocytes/macrophages and the expression of inflammatory and fibrotic markers in renal biopsies from 94 kidney recipients (60 DD and 34 LD) at baseline and 4 months after transplantation. We evaluated their association with medium- and long-term renal function. At baseline, inflammatory gene expression was higher in DD than in LD. These results were confirmed by the high number of CD68-positive cells in DD kidneys, which correlated negatively with long-term renal function. Expression of the fibrotic markers vimentin, fibronectin, and α-SMA was more elevated in biopsies from DD at 4 months than in LD. Gene expression of inflammatory and fibrotic markers at 4 months and difference between 4 months and baseline correlated negatively with medium- and long-term renal function in DD. Multivariate analysis point to TGF-β1 as the best predictor of long-term renal function in DD. We conclude that early macrophage infiltration, sustained inflammation and TGF-β1 expression, at least for the first 4 months, contribute significantly to the difference in DD and LD transplant outcome.

This review discusses the significance of genetics in diagnosing glomerular diseases. Advances in genetic testing, particularly next-generation sequencing, have improved the accessibility and accuracy of diagnosing monogenic diseases, allowing for targeted gene panels and whole-exome/genome sequencing to identify genetic variants associated with glomerular diseases. Key indicators for considering a genetic cause include the age of onset, extrarenal features, family history, and inconclusive kidney biopsy results. Early-onset diseases, for instance, have a higher likelihood of being genetically caused, while extrarenal manifestations can also suggest an underlying genetic condition. A thorough family history can reveal patterns of inheritance that point to monogenic causes, although complexities like incomplete penetrance, skewed X inactivation and mosaicism can complicate the assessment. Also, autosomal recessive conditions imply asymptomatic parents, making genetic suspicion less likely, while de novo mutations can occur without any family history, further obscuring genetic assessment. Focal segmental glomerulosclerosis (FSGS) is characterized by podocyte injury and depletion, presenting in various forms, including primary, genetic, and secondary FSGS. Accurate classification of FSGS patients based on clinical and histological features is essential for guiding treatment decisions, optimizing therapeutic plans, avoiding unnecessary immunosuppression, and predicting relapse risk after kidney transplantation. Overall, a clinicopathological approach, enriched by genetic testing, offers a precise framework for diagnosis and management in glomerular diseases. Future directions for research and clinical practice include potential advancements in genetic testing and personalized medicine, which could further improve diagnostic precision and individualized treatment strategies.