Immune-mediated Glomerular Disease Research Articles

Cardiotrophin-1 therapy reduces disease severity in a murine model of glomerular disease.

Cardiotrophin-1 (CT-1), a member of the interleukin (IL)-6 cytokine family, has renoprotective effects in mouse models of acute kidney disease and tubulointerstitial fibrosis, but its role in glomerular disease is unknown. To address this, we used the mouse model of nephrotoxic nephritis to test the hypothesis that CT-1 also has a protective role in immune-mediated glomerular disease. Using immunohistochemistry and analysis of single-cell RNA-sequencing data of isolated glomeruli, we demonstrate that CT-1 is expressed in the glomerulus in male mice, predominantly in parietal epithelial cells and is downregulated in mice with nephrotoxic nephritis. Furthermore, analysis of data from patients revealed that human glomerular disease is also associated with reduced glomerular CT-1 transcript levels. In male mice with nephrotoxic nephritis and established proteinuria, administration of CT-1 resulted in reduced albuminuria, prevented podocyte loss, and sustained plasma creatinine, compared with mice administered saline. CT-1 treatment also reduced fibrosis in the kidney cortex, peri-glomerular macrophage accumulation and the kidney levels of the pro-inflammatory mediator complement component 5a. In conclusion, CT-1 intervention therapy delays the progression of glomerular disease in mice by preserving kidney function and inhibiting renal inflammation and fibrosis.

#2167 Polyclonal immunoglobulin free light chains: an evidence of cardiac remodeling in patients with glomerular diseases

Abstract Background and Aims It was previously shown, that polyclonal immunoglobulin free light chains (FLC) are the independent predictor of mortality in patients with decompensated heart failure, chronic kidney disease (CKD) and also in general population. Mechanisms of this phenomenon are still unknown. The aim of our study is to reveal the possible relationships between FLC and cardiac remodeling in patients with glomerular diseases. Method We included 97 patients with biopsy-proven diagnosis of different immune-mediated glomerular diseases, 53% were men, mean age was 48 ± 14.6 years. Serum Freelite FLC levels were measured as well as standard clinical and laboratory investigation. At the time of biopsy transthoracic echocardiography was also performed. Glomerular filtration rate (eGFR) was estimated by “2021 CKD-EPI Creatinine” equation. Results Median of eGFR was 46.8 ml/min/1.73 m² (28.7-80.0), FLC-kappa level was 27.4 mg/l (16.8- 48.4), FLC-lambda level was 28.2 mg/l (20.8-43.3). FLC-kappa levels were above reference range in 65%, FLC-lambda levels – in 54%. LV diastolic dysfunction (DD) was present in 68%. Comparison in groups showed that the elevation of FLC-kappa more than 19.4 mg/l was associated with bigger LV mass index (LVMI) – 138.3 ± 30.2 g/m² vs 99.9 ± 31.2 g/m² р = 0.022, the parallel correlation was found between LVMI and levels of FLC-lambda higher than 26.3 mg/l (136.2 ± 64.8 g/m² vs 104.0 ± 36.6 g/m², р = 0.023). Spearman analysis has shown statistically significant correlations between FLC levels and E/e’- Rs = 0.501 p = 0.0001 for FLC-kappa, Rs = 0.343 p = 0.012 for FLC-lambda. Combined FLC level higher than 52.9 mg/l was a significant predictor of DD with area under the ROC curve (AUC) 0.703 (sensitivity 76.5%, specificity 62.5%). Conclusion Elevation of serum pFLC level could be a promising marker of cardiac remodeling, especially, of DD in patients with glomerular diseases. Possible pathogenic role of FLC in cardiorenal relationships may be revealed in further studies.

Automatic classification of immune-mediated glomerular diseases based on multi-modal multi-instance learning

To develop a multi-modal deep learning method for automatic classification of immune-mediated glomerular diseases based on images of optical microscopy (OM), immunofluorescence microscopy (IM), and transmission electron microscopy (TEM). We retrospectively collected the pathological images from 273 patients and constructed a multi-modal multi- instance model for classification of 3 immune-mediated glomerular diseases, namely immunoglobulin A nephropathy (IgAN), membranous nephropathy (MN), and lupus nephritis (LN). This model adopts an instance-level multi-instance learning (I-MIL) method to select the TEM images for multi-modal feature fusion with the OM images and IM images of the same patient. By comparing this model with unimodal and bimodal models, we explored different combinations of the 3 modalities and the optimal methods for modal feature fusion. The multi-modal multi-instance model combining OM, IM, and TEM images had a disease classification accuracy of (88.34±2.12)%, superior to that of the optimal unimodal model [(87.08±4.25)%] and that of the optimal bimodal model [(87.92±3.06)%]. This multi- modal multi- instance model based on OM, IM, and TEM images can achieve automatic classification of immune-mediated glomerular diseases with a good classification accuracy.

Rituximab Resistance in Glomerular Diseases: A GlomCon Mini Review

Resistance to rituximab B-cell depletion therapy is a clinically pertinent adverse sequela, which can have significant implications for the treatment of immune-mediated glomerular diseases. The true incidence of rituximab resistance remains unknown, however, it is an increasingly recognized treatment complication. Resistance typically presents with suboptimal treatment response, rapid B-cell reconstitution, and a relapsing disease course. While the diverse mechanisms resulting in rituximab resistance are ongoing topics of research, both primary and secondary mechanisms have been identified as key catalysts.The emergence of human anti-chimeric antibodies (HACA) is a major cause of secondary resistance to rituximab therapy and typically appears following repeated drug exposure. Frequently, HACA develop in the setting of underlying autoimmune disease and contribute to poor B-cell depletion, reduced rituximab therapeutic efficacy, and enhanced drug clearance.The clinical challenge of rituximab resistance necessitates heightened awareness among clinicians. Screening for HACA should be considered in individuals with poor clinical response to rituximab, more rapid B-cell reconstitution, and relapsing disease. Detection of HACA may guide treatment alterations, including addition of further immunosuppressive therapy and transitioning to a humanized B-cell depleting monoclonal antibody.

Lactobacillus species ameliorate membranous nephropathy through inhibiting the aryl hydrocarbon receptor pathway via tryptophan-produced indole metabolites.

Membranous nephropathy (MN) is an immune-mediated glomerular disease in adults. Antibody- and antigen-bonding mechanisms have been largely clarified, but the subepithelium immune complex deposition-mediated downstream molecular mechanisms are currently unresolved. Increasing evidence has suggested that gut microbiota contribute to MN pathogenesis. In this study, we identified alterations in faecal gut microbiota and serum metabolites that mediate an aryl hydrocarbon receptor (AhR) mechanism in cationic bovine serum albumin (CBSA)-induced MN rats and in patients with idiopathic MN (IMN). Impaired renal function correlated with the relative abundance of reduced faecal probiotics, Lactobacillus and Bifidobacterium, and altered serum levels of tryptophan-produced indole derivatives (TPIDs) in MN rats. Further results showed that reduced relative abundance of five probiotics, namely Lactobacillus johnsonii, Lactobacillus murinus, Lactobacillus vaginalis, Lactobacillus reuteri and Bifidobacterium animalis, positively correlated with decreased levels of indole-3-pyruvic acid, indole-3-aldehyde and tryptamine and negatively correlated with increased levels of indole-3-lactic acid and indole-3-acetic acid in serum of MN rats. Altered five probiotics and five TPIDs also were observed in patients with IMN. Further studies showed that MN rats exhibited a significant increase in intrarenal mRNA expression of AhR and its target genes CYP1A1, CYP1A2 and CYP1B1, which were accompanied by protein expression of down-regulated cytoplasmic AhR, but up-regulated nuclear AhR, in MN rats and IMN patients. Activation of the intrarenal AhR signalling pathway may involve five TPIDs. These data suggest that gut microbiota could influence MN through TPIDs that engage host receptors.

COVID-19 outcomes in patients with a history of immune-mediated glomerular diseases.

Patients with immune-mediated glomerular diseases are considered at high risk for severe COVID-19 outcomes. However, conclusive evidence for this patient population is scarce. We created a global registry and retrospectively collected clinical data of patients with COVID-19 and a previously diagnosed immune-mediated glomerular disease to characterize specific risk factors for severe COVID-19 outcomes. Fifty-nine patients with a history of immune-mediated glomerular diseases were diagnosed with COVID-19 between 01.03.2020 and 31.08.2021. Over a mean follow-up period of 24.79 ± 18.89 days, ten patients (16.9%) developed acute kidney injury. Overall, 44.1% of patients were managed in an outpatient setting and therefore considered as having "non-severe" COVID-19, while 55.9% of patients had severe COVID-19 requiring hospitalization including worse outcomes. Comparing both groups, patients with severe COVID-19 were significantly older (53.55 ± 17.91 versus 39.77 ± 14.95 years, p = .003), had lower serum albumin levels at presentation (3.00 ± 0.80 g/dL versus 3.99 ± 0.68 g/dL, p = .016) and had a higher risk of developing acute kidney injury (27% versus 4%, p = .018). Male sex (p <.001) and ongoing intake of corticosteroids at presentation (p = .047) were also significantly associated with severe COVID-19 outcomes, while the overall use of ongoing immunosuppressive agents and glomerular disease remission status showed no significant association with the severity of COVID-19 (p = .430 and p = .326, respectively). Older age, male sex, ongoing intake of corticosteroids and lower serum albumin levels at presentation were identified as risk factors for severe COVID-19 outcomes in patients with a history of various immune-mediated glomerular diseases.

Present and Future of IgA Nephropathy and Membranous Nephropathy Immune Monitoring: Insights from Molecular Studies.

IgA Nephropathy (IgAN) and Membranous Nephropathy (MN) are primary immune-mediated glomerular diseases with highly variable prognosis. Current guidelines recommend that greater immunologic activity and worse prognosis should guide towards the best treatment in an individualized approach. Nevertheless, proteinuria and glomerular filtration rate, the current gold standards for prognosis assessment and treatment guidance in primary glomerular diseases, may be altered with chronic damage and nephron scarring, conditions that are not related to immune activity. In recent years, thanks to the development of new molecular technologies, among them genome-wide genotyping, RNA sequencing techniques, and mass spectrometry, we have witnessed an outstanding improvement in understanding the pathogenesis of IgAN and MN. In addition, recent genome-wide association studies have suggested potential targets for immunomodulating agents, stressing the need for the identification of specific biomarkers of immune activity. In this work, we aim to review current evidence and recent progress, including the more recent use of omics techniques, in the identification of potential biomarkers for immune monitoring in IgAN and MN.

CD4+ T cells produce GM-CSF and drive immune-mediated glomerular disease by licensing monocyte-derived cells to produce MMP12.

GM-CSF in glomerulonephritisDespite glomerulonephritis being an immune-mediated disease, the contributions of individual immune cell types are not clear. To address this gap in knowledge, Paust etal. characterized pathological immune cells in samples from patients with glomerulonephritis and in samples from mice with the disease. The authors found that CD4+ T cells producing granulocyte-macrophage colony-stimulating factor (GM-CSF) licensed monocytes to promote disease by producing matrix metalloproteinase 12 and disrupting the glomerular basement membrane. Targeting GM-CSF to inhibit this axis reduced disease severity in mice, implicating this cytokine as a potential therapeutic target for patients with glomerulonephritis. -CM.

The evolving landscape of immune-mediated glomerular diseases.

The evolving landscape of immune-mediated glomerular diseases.

Change of circulating lymphocyte subsets is related to disease activity and secondary infection in children with primary nephrotic syndrome-a retrospective study.

Primary nephrotic syndrome (PNS) is an immune-mediated glomerular disease that often reoccurs. However, the characteristics of circulating lymphocyte subsets in PNS children remain unclear. Immunosuppressive therapy can lead to temporary or persistent remissions, but also increases the risk of infection, and whether the circulating lymphocyte subsets can be used to predict the secondary infection also remains unclear. Here, we explored the distribution of lymphocyte subpopulations in the different stages of PNS, and its predictive value of secondary infection in pediatric patients. We included 89 children who were first PNS episodes or diagnosed with PNS admitted to Nanfang Hospital from September 2019 to April 2021, and 19 healthy children were recruited as controls (C). PNS patients were divided into three groups according to their serum biochemical tests: active group (A), partial remission (PR) group, and complete remission (CR) group. PNS patients with infection symptoms were divided into a co-infection group, others were divided into the non-infection group. The peripheral lymphocyte subsets were analyzed by flow cytometry. The relationship between the peripheral lymphocyte subsets and PNS activity or infection was analyzed. Compared to the healthy controls, the PNS patients' CD8+CD28+ T cell (TC) (C: 16.6%, 450.8/µL; A: 29.1%, P=0.000, 886.1/µL, P=0.012; PR: 25.7%, P=0.000, 817.3/µL, P=0.012; CR: 24.9%, P=0.001, 747.9/µL, P=0.020), and CD4+CD45RO+ ("memory" helper) T cells (C: 13.2%, 358.9/µL; A: 15.7%, P=0.036, 578.7/µL, P=0.001; PR: 17.6%, P=0.002, 610.0/µL, P=0.000; CR: 13.7%, P=0.676, 398.1/µL, P=0.525) were elevated. In addition, the regulatory T cells counts (non-infection: 117.9/µL; Co-infection: 73.3/µL, P=0.001) were significantly lower in patients with infection. We found that the predictive value measured by the area under the curve (AUC) showed that the AUC (t) Treg cell counts (61.5-84.5%) were almost always higher than the AUC for the (t) CD4+ T cell counts (55.1-77.1%). In this study, we found that T cell subpopulations had different characteristics in PNS during different disease phases. The CD8+CD28+ T cells, and CD4+CD45RO+ T cells increased at the disease quiescence of PNS. Moreover, CD4+ T cell subsets (regulatory T cell <82.5/µL) had higher predictive value than CD4+ T cell counts for PNS infection.

Modern view on the complement system role in membranous nephropathy

Membranous nephropathy (MN), an immune-mediated glomerular disease, is the most common cause of adult nephrotic syndrome. In MN, proteinuria is developed by podocyte damage due to the complement system activation in response to the subepithelial deposition of immune complexes containing various auto- and exogenous antigens. Membrane-attacking complex (MAC) is the terminal product of any complement pathways activation (classical, lectin or alternative) and plays the leading role in the complement-mediated podocytic damage. Thus far, the main pathway of complement activation leading to the formation of MAC in MN has not been established. The review highlights current evidence of various complement pathways activation in the development of MN, as well as recently established new molecular mechanisms of complement-mediated podocyte damage.

Plasma Galectin-9 Is a Useful Biomarker for Predicting Renal Function in Patients Undergoing Native Kidney Biopsy.

Galectin-9 reduces tissue damage in certain immune-mediated glomerular diseases. However, its role in structural and functional renal changes in patients with varying types of chronic kidney disease (CKD) is less clear. To investigate the association between plasma galectin-9 levels, proteinuria, tubulointerstitial lesions, and renal function in different CKD stages. We measured plasma galectin-9 levels in 243 patients undergoing renal biopsy for determining the CKD etiology. mRNA and protein expression levels of intrarenal galectin-9 were assessed by quantitative real-time polymerase chain reaction and immunostaining. Relationships between plasma galectin-9, clinical characteristics, and tubulointerstitial damage were analyzed with logistic regression. We investigated galectin-9 expression patterns in vitro in murine J774 macrophages treated with differing stimuli. To analyze the relationship between galectin-9 and clinical features, we divided the patients into 2 groups according to median plasma galectin-9 levels. The high galectin-9 group tended to be older and to have decreased renal function, higher proteinuria, and greater interstitial fibrosis. After multivariable adjustment, elevated plasma galectin-9 levels were independently associated with stage 3b or higher CKD. An analysis of gene expression in the tubulointerstitial compartment in the biopsy samples showed a significant positive correlation between intrarenal galectin-9 mRNA expression and plasma galectin-9 levels. Immunohistochemistry confirmed increased galectin-9 expression in the renal interstitium of patients with advanced CKD, and most galectin-9-positive cells were macrophages, as determined by double-immunofluorescence staining. In vitro experiments showed that galectin-9 expression in macrophages was significantly increased after interferon-γ stimulation. Our findings suggest that plasma galectin-9 is a good biomarker for diagnosing advanced CKD.

Antigen Cross-Presentation by Murine Proximal Tubular Epithelial Cells Induces Cytotoxic and Inflammatory CD8+ T Cells.

Immune-mediated glomerular diseases are characterized by infiltration of T cells, which accumulate in the periglomerular space and tubulointerstitium in close contact to proximal and distal tubuli. Recent studies described proximal tubular epithelial cells (PTECs) as renal non-professional antigen-presenting cells that stimulate CD4+ T-cell activation. Whether PTECs have the potential to induce activation of CD8+ T cells is less clear. In this study, we aimed to investigate the capacity of PTECs for antigen cross-presentation thereby modulating CD8+ T-cell responses. We showed that PTECs expressed proteins associated with cross-presentation, internalized soluble antigen via mannose receptor-mediated endocytosis, and generated antigenic peptides by proteasomal degradation. PTECs induced an antigen-dependent CD8+ T-cell activation in the presence of soluble antigen in vitro. PTEC-activated CD8+ T cells expressed granzyme B, and exerted a cytotoxic function by killing target cells. In murine lupus nephritis, CD8+ T cells localized in close contact to proximal tubuli. We determined enhanced apoptosis in tubular cells and particularly PTECs up-regulated expression of cleaved caspase-3. Interestingly, induction of apoptosis in the inflamed kidney was reduced in the absence of CD8+ T cells. Thus, PTECs have the capacity for antigen cross-presentation thereby inducing cytotoxic CD8+ T cells in vitro, which may contribute to the pathology of immune-mediated glomerulonephritis.

Conventional NK Cells and Type 1 Innate Lymphoid Cells Do Not Influence Pathogenesis of Experimental Glomerulonephritis.

Innate lymphoid cells (ILCs) that express NK cell receptors (NCRs) and the transcription factor T-bet populate nonlymphoid tissues and are crucial in immune responses against viral infections and malignancies. Recent studies highlighted the heterogeneity of this ILC population and extended their functional spectrum to include important roles in tissue homeostasis and autoimmunity. In this article, we provide detailed profiling of NCR+T-bet+ ILC populations in the murine kidney, identifying conventional NK (cNK) cells and type 1 ILCs (ILC1s) as the two major subsets. Induction of renal inflammation in a mouse model of glomerulonephritis did not substantially influence abundance or phenotype of cNK cells or ILC1s in the kidney. For functional analyses in this model, widely used depletion strategies for total NCR+ ILCs (anti-NK1.1 Ab application) and cNK cells (anti-asialoGM1 serum application) were unreliable tools, because they were accompanied by significant off-target depletion of kidney NKT cells and CD8+ T cells, respectively. However, neither depletion of cNK cells and ILC1s in NKT cell-deficient mice nor specific genetic deletion of cNK cells in Ncr1 Cre/wt × Eomes fl/fl mice altered the clinical course of experimental glomerulonephritis. In summary, we show in this article that cNK cells and ILC1s are dispensable for initiation and progression of immune-mediated glomerular disease and advise caution in the use of standard Ab depletion methods to study NCR+ ILC function in mouse models.

Use of Rituximab as an Off-Label Medication in Glomerular Diseases: Clinical Perspective

Objectives: The aim of this study was to review the use rituximab (RTX) and outcomes in immune-mediated glomerular diseases (glomerulonephritis [GN]) and to compare it to the established literature. Methods: Adult GN patients who received RTX between January 2014 and January 2018 in three public hospitals were reviewed. Membranous nephropathy (MN) and minimal change disease (MCD) were considered diseases with the literature supporting RTX use. Lupus nephritis (LN), primary focal segmental glomerulosclerosis (1^o FSGS), IgA nephropathy, IgG4-related disease (IgG4-RD), and C3GN had insufficient literature support for RTX use. Clinical remission was assessed 6 months after receiving RTX. Results: A total of 61 cases were analyzed. RTX was an add-on therapy in 87%. The remission rate was 95% in the MCD and MN versus 56% in the off-label group (p = 0.002). LN patients had a mean initial estimated glomerular filtration rate (eGFR) of 69 mL/min. All class III LN achieved remission, and 11 of 21 class IV achieved remission. The mean initial eGFR for 1^o FSGS was 33 mL/min, and it did not improve, and only 2 of 5 had partial resolution of proteinuria. Proteinuria improved in 3 of 5 IgG4-RD cases with eGFR stabilization but failed to improve in C3GN cases with eGFR deterioration. Vasculitis cases (6 ANCA-associated vasculitis and 2 IgA vasculitis) were analyzed separately. Remission was achieved in only 2 ANCA-associated vasculitis cases, and none in IgA vasculitis cases. Conclusions: Our data support the use of RTX in resistant MCD and MN. RTX showed success in LN and IgG4-RD but not FSGS or C3GN. The small number of cases of vasculitis does not allow drawing a conclusion on RTX effectiveness.

Serum WNT4 protein as an indicator of chronic glomerulonephritis but not a marker of inflammatory cell infiltration and fibrosis: A preliminary study

The WNT signaling pathway contributes to renal fibrosis, which is a hallmark of chronic kidney disease (CKD). Serum concentration of WNT4 could be used to monitor the kidney disease; however, no data have yet been published on the subject. This study measures WNT4 protein in serum of CKD patients depending on the stage, type of nephropathy, the non-nephrotic (NNP) or nephrotic proteinuria (NP), inflammatory cell infiltration in kidney parenchyma (IIKP), interstitial fibrosis in biopsy and serum creatinine. We also evaluated the usefulness of the serum WNT4 as a marker of fibrosis and IIKP. The WNT4 protein level in serum of CKD patients and healthy individuals was measured using enzyme-linked immunoassay (ELISA). Patients' blood biochemical profiles and kidney biopsies were evaluated with common laboratory methods. The serum level of WNT4 protein was higher in CKD patients (i) regardless of the underlying etiology and at early stages of disease; (ii) with lupus nephritis and Immunoglobulin A (IgA) nephropathy; (iii) without or with a small area of IIKP; and (iv) with a small area covered with fibrosis. No difference was observed between NNP and NP patients. The utility of serum WNT4 as a marker of IIKP and fibrosis was not confirmed. Negative correlations with total and low-density lipoprotein (LDL)-cholesterol were found in CKD and IIKP patients. In patients with serum WNT4 above the median value, serum creatinine was higher. However, no correlation between serum WNT4 and creatinine level was found. The observed increase in serum WNT4 protein in the early stages of CKD and in patients diagnosed with immune-mediated glomerular disease may suggest that WNT4 may act as a mediator of inflammation. A certain association with the dysregulation of serum lipid metabolism can also be suspected. Serum WNT4 protein may be considered as the indicator of chronic glomerulonephritis, but not a diagnostic marker of IIKP and fibrosis.

How immunosuppressive drugs may directly target podocytes in glomerular diseases.

Podocytes are the direct target of immunologic injury in many immune-mediated glomerular diseases, leading to proteinuria and subsequent kidney failure. Immunosuppressive agents such as steroids, calcineurin inhibitors, and rituximab are the commonly used treatment strategies in this context for their immunotherapeutic or anti-inflammatory properties. However, in recent years, studies have demonstrated that immunosuppressive agents can have a direct effect on podocytes, introducing the concept of the non-immunologic mechanism of kidney protection by immunomodulators. In this review, we focus on the mechanisms by which these agents may directly target the podocyte independent of their systemic effects and examine their clinical significance.

MO316RITUXIMAB IN GLOMERULAR DISEASES: A COHORT ANALYSIS AND A LITERATURE REVIEW

Abstract Background and Aims Glomerular diseases (GD) account for about 20% of chronic kidney disease causes. They are a heterogeneous group of diseases and current treatment is still inadequate. Rituximab (RTX) is a chimeric antibody which binds specifically to the B-cell surface antigen CD20 and has been applied in the treatment of different GD. The authors present the single center experience of the use of RTX for the treatment of GD as well as a literature review. Method We performed a retrospective analysis of all patients with biopsy-proven GD treated with RTX as first or second-line therapy between January 2010 and March 2020. The protocol used was RTX 375 mg/m2 once a week for 4 weeks. Infusions were preceded by adequate premedication. Results Nineteen patients with biopsy-proven GD received RTX therapy. Seven patients had membranous nephropathy (MN) (36.8%), 4 patients had focal segmental glomerulosclerosis (FSGS), 4 patients had lupus nephritis (LN) and 4 patients had vasculitis (25.0% each). Five patients (26.3%) received RTX as first-line therapy and 14 patients (73.7%) as second-line therapy, namely long-term prednisolone (Pd) (n=15, 78.9%), calcineurin inhibitors (CNI) (n=6, 31.6%), cyclophosphamide (Cp) (n=7, 36.8%), mycophenolate mofetil (MMF) (n=5, 26.3%) and methotrexate (MTX) (n=1, 5.3%). Serum creatinine at diagnosis was 1.5 ± 1.7mg/dL and the 24-h urine protein at diagnosis was 4.9 ± 4.5g. Mean follow-up time was 7.7 ± 7.2 years. In MN, 2 patients (28.6%) had CR, 2 patients (28.6%) had PR and 3 patients (42.9%) had no response. In FSGS, 2 patients (50.0%) presented CR, 1 patient (25.0%) had no response and the other one had renal deterioration. Two patients (50.0%) had a LN class IV with a CR after RTX, 1 patient with LN class IIIC/V had no response and 1 patient with LN class II had renal deterioration. In vasculitis, 3 patients (75.0%) presented CR and 1 patient had PR. Mean serum creatinine after RTX was 1.6 ± 1.4mg/dL and the mean 24-h urine protein was 1.9 ± 3.1g. Two patients (10.5%) presented infusion reactions and one patient had multiple respiratory infections. This patient had received previous immunosuppression with cyclophosphamide. Conclusions A total of 19 patients with biopsy-proven GD received RTX therapy and 12 patients (63.2%) presented a complete or partial remission suggesting the efficacy of RTX in different types of GD. In MN, our response rate was similar to studies such as GEMRITUX and MENTOR trial, which have shown remission in 60–70% of patients. In FSGS, 50% of patients had a stable and complete remission with RTX therapy similar with a meta-analysis of five studies with 51 patients with FSGS. Two patients had refractory LN class IV and both had complete remission (50% of patients with LN). This is in line with a systematic review of case reports and case series that reported sustained complete and partial response rates of 67% in LN class IV. In our cohort, patients with vasculitis received RTX as first-line therapy and complete remission was achieved in 75% of cases, which is in line with the results found in RITUXVAS and RAVE trial. Rituximab was safe and effective in achieving remission in different types of immune-mediated glomerular diseases.

Circulating plasmablasts and high level of BAFF are hallmarks of minimal change nephrotic syndrome in adults.

The recent success achieved with the use of B cell-depleting agents in some patients with minimal change nephrotic syndrome (MCNS) suggests an unexpected role for B lymphocytes in the pathogenesis of this immune-mediated glomerular disease. Nevertheless, no extensive B-cell phenotyping analysis has ever been performed in untreated adult patients soon after MCNS diagnosis. We investigated the distribution of the different B-cell subpopulations in 22 untreated adult patients with biopsy-proven MCNS [MCNS relapse (MCNS-Rel)]. We compared these data with those for 24 healthy controls, 13 MCNS patients in remission (with no specific treatment) and 19 patients with idiopathic membranous nephropathy (IMN). Patients with MCNS-Rel or IMN had higher proteinuria and lower serum albumin and gammaglobulin levels (P < 0.0001 for all comparisons) than MCNS patients in remission. Plasmablasts were the only B-cell subsets present at significantly higher levels in MCNS-Rel patients than in the patients of the other three groups (P < 0.05 for all comparisons). The lower albumin levels and higher proteinuria levels were positively correlated with the percentage of circulating plasmablasts (Spearman test's ρ = -0.54, P = 0.01 and ρ = 0.65, P = 0.002, respectively). Similarly, the increase of immunoglobulin M (IgM) and the decrease of IgG levels were significantly associated with the percentage of plasmablasts in MCNS-Rel patients (Spearman's ρ = 0.36, P = 0.01 and Spearman's ρ = -0.60, P = 0.01, respectively). Increased production of interleukin (IL)-21, IL-6 and B-cell activating factor (BAFF) in the serum of MCNS-Rel patients was found significantly correlated with the percentage of plasmablasts (ρ = 0.72, P = 0.0002, ρ = 0.49, P = 0.04 and ρ = 0.62, P = 0.009, respectively). An increase in the proportion of circulating plasmablasts seems to be a hallmark of untreated MCNS in adult patients. Further studies are required to more precisely determine the phenotype and functions of these cells.

Podocytes present antigen to activate specific T cell immune responses in inflammatory renal disease.

Infiltration of activated T cells into renal tissue plays an essential role in inflammatory nephropathy. However, the mechanism enabling the renal recruitment and activation of T cells remains elusive. Here we report that inflammatory cytokine-promoted antigen presentation by podocytes is a key for recruiting and activating specific T cells. Our results showed that diabetes-associated inflammatory cytokines IFNγ and IL-17 all upregulated expression of MHC-I, MHC-II, CD80 and CD86 on the podocyte surface. Both IFNγ and IL-17 stimulated the uptake and processing of ovalbumin (OVA) by mouse podocytes, resulting in presentation of OVA antigen peptide on the cell surface. OVA antigen presentation by podocytes was also validated using human podocytes. Furthermore, OVA antigen-presenting mouse podocytes were able to activate OT-I mouse T cell proliferation and inflammatory cytokine secretion, which in turn caused podocyte injury and apoptosis. Finally, OT-I mice subjected to direct renal injection of OVA plus IFNγ/IL-17 but not OVA alone exhibited OVA antigen presentation by podocytes and developed nephropathy in 4 weeks. In conclusion, antigen presentation by podocytes under inflammatory conditions plays an important role in activating T cell immune responses and facilitating immune-mediated glomerular disease development. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.