Background Semaphorin-3B (SEMA3B)–associated membranous nephropathy (MN) is a recently described, antigen-defined subtype of MN, predominantly reported in pediatric patients, but also in young adults. Cases of post-kidney transplant recurrent SEMA3B-associated have also been reported in both children and adults. Case Presentation We report a 40-year-old woman who presented with nephrotic syndrome and was concurrently diagnosed with celiac disease. Kidney biopsy demonstrated stage I membranous nephropathy with IgG-dominant immune deposits and negative serum anti-PLA2R antibodies. Despite a gluten-free diet, optimized supportive therapy, and corticosteroid treatment, nephrotic-range proteinuria persisted. Rituximab therapy resulted in complete clinical remission. Subsequent laser microdissection and mass spectrometry analysis of the kidney biopsy identified SEMA3B as the target antigen, establishing the diagnosis of SEMA3B-associated MN. Conclusions This case highlights that adult-onset SEMA3B-associated membranous nephropathy may coexist with autoimmune disorders that complicate etiologic interpretation. Antigen identification by laser microdissection and mass spectrometry provided retrospective clarification of the underlying disease process and supported classification within the current antigen-based framework. This case illustrates the value of antigen identification in PLA2R-negative membranous nephropathy when alternative etiologies are being considered.

INTRODUCTION:Hematuria is a hallmark clinical manifestation of IgA nephropathy (IgAN) and largely reflects underlying glomerular inflammation. Despite this, current guidelines prioritize proteinuria and estimated glomerular filtration rate for risk assessment, and the association between urinary findings and underlying histologic lesions remains incompletely characterized. METHODS:Here, we conducted a multicenter retrospective cohort study of patients with biopsy-proven IgAN (July 2015-July 2025) with concurrent urinalysis. Associations between hemoglobinuria (dipstick), hematuria (microscopy), proteinuria and individual Oxford Classification MEST-C components, and composite inflammatory lesions (M1, E1, and/or C1/C2; and E1 and/or C1/C2) were evaluated using unadjusted cohort-specific logistic regression models. Pooled odds ratios (ORs) were estimated using random-effects meta-analysis. RESULTS:Among 441 patients, hemoglobinuria was associated with M1 lesions (pooled OR 1.77, 95% CI 1.25-2.51), E1 lesions (1.75, 1.44-2.11), and crescentic lesions (1.57, 1.20-2.07). Hematuria was also associated with M1 lesions (1.24, 1.14-1.35), E1 lesions (1.22, 1.13-1.31), and C1/C2 lesions (1.18, 1.09-1.28). For the composite outcome (M1, E1, and/or C1/C2), pooled ORs were 2.28 (1.76-2.97) for hemoglobinuria, 1.36 (1.22-1.51) for hematuria, and 1.20 (1.04-1.38) for proteinuria. Hemoglobinuria and hematuria were not associated with chronic lesions, whereas proteinuria was consistently associated with T1/T2 lesions (1.35, 1.20-1.52). CONCLUSIONS:Dipstick hemoglobinuria is associated with histologic markers of active disease in IgAN and may provide clinically relevant information to complement current assessment of disease activity in IgAN.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but are associated with immune-related adverse events (irAEs), including kidney injury. While acute interstitial nephritis is the most common renal irAE, glomerular diseases such as IgA vasculitis remain rare and poorly characterized. We report the first biopsy-confirmed case of IgA vasculitis with crescentic glomerulonephritis associated with the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab (ATZ). A 75-year-old man with metastatic small-cell neuroendocrine prostate carcinoma developed a skin palpable purpuric rash after ATZ exposure treated with topical corticosteroids, with subsequent development of acute kidney injury. Kidney biopsy demonstrated IgA-dominant necrotizing and crescentic glomerulonephritis, consistent with IgA vasculitis. High-dose oral and intravenous corticosteroids resulted in only partial renal improvement and persistent systemic inflammation. Subsequent treatment with rituximab (RTX) led to sustained stabilization of kidney function, normalization of previously elevated inflammatory cytokines (TNF-α, IL-18, soluble IL-2 receptor), and complete peripheral B-cell depletion. Although the malignancy later progressed, renal function remained stable following RTX therapy. This case highlights IgA vasculitis as a rare but serious renal complication of PD-L1 inhibition and supports rituximab as a potential rescue therapy in corticosteroid-refractory cases. Careful biomarker monitoring and multidisciplinary management are essential to balance renal protection with oncologic outcomes.

Resumo A glomerulopatia C3 (C3G) é uma entidade clinicopatológica caracterizada por inflamação glomerular com dominância de C3 à imunofluorescência. A microscopia eletrônica é utilizada para determinar a localização e o tipo de depósitos, o que permite subdividir a C3G em glomerulonefrite C3 (GNC3) e doença de depósitos densos (DDD) com base em achados ultraestruturais. Ambas as entidades são progressivas, com cerca de 60% dos pacientes evoluindo para doença renal terminal (DRT) em 10 anos. A recorrência após o transplante renal ocorre em até 60% dos casos de C3G. Novos conhecimentos sobre a fisiopatologia—diferentes padrões de lesão, escores histopatológicos, coloração para apolipoproteína E, desregulação da via alternativa do complemento, que inclui autoanticorpos e mutações em fatores reguladores do complemento, bem como análises proteômicas—permitiram uma melhor compreensão dos diferentes perfis fisiopatológicos e apresentações clínicas, possibilitando um tratamento individualizado. O papel da nefroproteção está bem estabelecido na C3G, assim como em outras doenças glomerulares. O tratamento não específico com corticosteroides e imunossupressores está associado a uma taxa de resposta variável. No entanto, mais recentemente, os resultados de ensaios clínicos com inibidores proximais da via alternativa do complemento demonstraram melhora significativa na proteinúria e atenuação da redução da taxa de filtração glomerular estimada (TFGe). Com base nos resultados desses ensaios com medicamentos que atuam especificamente nas vias do complemento a montante, incluindo a via alternativa, novas opções de tratamento tornaram-se disponíveis para pacientes com C3G.

Lupus nephritis represents one of the most severe manifestations of systemic lupus erythematosus. Despite major advances in the therapeutical armamentarium over the last two decades, the number of patients reaching end stage kidney disease or dying has not changed significantly. One of the main reasons is that many patients relapse, and with each relapse, further damage is done to the kidney, contributing to the development of progressive chronic kidney disease. This has led to the increased practice of doing protocol biopsy to guide decision regarding risk for relapses and/or discontinuation of immunosuppression. However, this practice has been based on the assumption that the answer is in the kidney, while in reality the kidney reflects the downgrade effect of what is going on upstream, i.e. the immunological milieu. We provide an in-dept review on the use of repeat protocol kidney biopsies in LN with the hope to demonstrate that this practice is based on faulty evidence and of limited benefit in the management of patients with proliferative class III/IV lupus nephritis. Rather, physicians treating these patients should focus on markers of immunological activity (anti-ds-DNA levels) and clinical activity (C3/C4 complement levels), to better predict risk for relapses and in deciding when to reduce/discontinue immunosuppression. As such, this review represents a paradigm shift in the approach of evaluating activity in patients with LN, that is not done by performing protocol kidney biopsies, but rather by looking at the serological activity instead, and as such proposing a new vision on the subject that we believe will improve patient care and kidney outcomes.

Membranoproliferative glomerulonephritis (MPGN) has undergone a change in classification that is focused on the etiology of MPGN. Thus, MPGN is classified into immune-complex (IC)-mediated MPGN and complement-mediated MPGN (C3 glomerulopathy) based on immunofluorescence microscopy studies that show positive staining for Igs and/or C3. IC-MPGN typically results from an infection or an autoimmune disease. Deposition of monotypic/monoclonal Ig also results in an MPGN. On the other hand, MPGN with bright C3 and minimal/no Ig is classified as C3 glomerulopathy. On the basis of the absence of any clinical evidence of an infection, autoimmune disease, or monoclonal gammopathy, the IC-MPGN is often labeled as primary/idiopathic MPGN. As such, increasing numbers of primary/idiopathic IC-MPGN are being diagnosed. In my renal biopsy practice, I have rarely seen an MPGN in an adult kidney biopsy in which I could not find an underlying etiology after diligent and careful evaluation of the biopsy. Some of the primary/idiopathic IC-MPGN falls into the monotypic/monoclonal Ig-associated MPGN, some into uncommon diseases, such as fibrillary glomerulonephritis, whereas others represent C3 glomerulopathy to begin with where the Ig is often entrapped in areas of scarring and does not represent true IC-MPGN. On the other hand, infection-related glomerulonephritis may be misclassified into C3 glomerulonephritis when there is sparse IgG on immunofluorescence microscopy. Chronic thrombotic microangiopathies can present with an MPGN pattern of injury and may be mislabeled as IC-MPGN or C3 glomerulonephritis from entrapment of IgM and/or C3. It is thus critical that we perform a thorough clinical and pathologic evaluation before labeling a case as idiopathic/primary IC-MPGN. Kidney biopsy evaluation should include complete immunofluorescence microscopy, including light chains, and electron microscopy. Pronase immunofluorescence microscopy and IgG subclass staining should be available to rule out masked Ig deposits and monotypic/monoclonal Ig-associated MPGN. An accurate diagnosis with identification of the etiology of IC-MPGN will allow for targeted treatment of the MPGN.

Introduction:The aim of this study was to evaluate the prognostic value of the Mayo Clinic Chronicity Score (MCCS) compared with the National Institutes of Health (NIH) Chronicity Index (NIH-CI) in lupus nephritis (LN). Methods:We conducted a retrospective cohort study of 307 patients with biopsy-proven LN evaluated at Mayo Clinic (1992-2023). Chronic histologic injury was graded using the NIH-CI and MCCS. Outcomes were proteinuria remission < 500 mg/d (PR500), complete renal response (CRR), end-stage kidney disease (ESKD), and all-cause mortality. Sex-stratified, age-adjusted Cox models were used. Prognostic performance was evaluated using change in Harrell's C-index (ΔC over a clinical model) and decision-curve analysis was used to assess clinical utility for 5-year ESKD. Subgroup analyses were used to test for effect modification by baseline estimated glomerular filtration rate (eGFR) (< 60 vs. ≥ 60 ml/min per 1.73 m2) and histologic class (proliferative vs. nonproliferative). Results:Higher NIH-CI and MCCS scores were associated with lower likelihood of PR500 and CRR (hazard ratio [HR]: 0.75 for both) and greater risk of ESKD (HR: 1.40 for NIH-CI; 1.33 for MCCS). Adding either score to a clinical model improved discrimination for PR500 (C-index: 0.65 to 0.71), CRR (0.64 to 0.71), and ESKD (0.81 to 0.85), but not mortality (ΔC = 0.00). Decision-curve analysis showed similar net benefits for NIH-CI and MCCS. Interstitial fibrosis (IF) and tubular atrophy (TA) (IF/TA) were the only components independently predictive of renal outcomes. Our findings support applicability of both scores in nonproliferative LN and in patients with reduced baseline kidney function. Conclusion:The MCCS and NIH-CI provide comparable and additive prognostic information in LN. MCCS captured the chronic lesions most strongly associated with renal outcomes, with IF/TA as the principal determinant of prognosis.

BACKGROUND:Sodium-glucose co-transporter 2 inhibitors (SGLT2is) are emerging as an essential part of the standard of care for proteinuria in patients with chronic kidney disease. To date, no study has specifically evaluated the effects of body mass index (BMI) on the antiproteinuric efficacy of SGLT2is. Here we report the impact of BMI on the antiproteinuric efficacy of SGLT2is in non-diabetic patients with glomerular diseases. METHODS:This is a retrospective, multicentre, international observational cohort study that included non-diabetic patients with biopsy-proven glomerular disease and proteinuria >0.5 g/24 h who received SGLT2is between 2016 and 2023. Laboratory values, including proteinuria and estimated glomerular filtration rate (eGFR), were obtained at baseline and after 3-6 months. Changes in laboratory values over time were analysed using the paired signed-rank test. RESULTS:A total of 300 patients met the inclusion criteria. The median age was 51.82 years [interquartile range (IQR) 41-62.65], 64.7% were male and 92.7% were white. The most common glomerular disease was immunoglobulin A nephropathy (40.3%). The median eGFR was 52.26 ml/min/1.73 m2 (IQR 36.41-74.01), the median proteinuria was 1.60 g/24 h (IQR 1.15-2.91) and the median serum albumin was 4.08 g/dl (IQR 3.80-4.30). Proteinuria reduction after SGLT2i initiation was significant only in overweight and obese patients (P < .001 versus 0.18). Patients with normal BMI did not experience the expected early decrease in eGFR (P = .16). CONCLUSIONS:SGLT2is are ineffective in proteinuria reduction in patients with a BMI <25 kg/m2, which contrasts with the significant proteinuria reduction in overweight and obese patients with glomerulopathies.

C3 glomerulonephritis (C3GN) is a rare kidney disease driven by dysregulation of the alternative complement pathway. We report two challenging cases of patients with C3GN in whom various immunosuppressant therapies have failed to achieve complete remission, prompting treatment with eculizumab, an anti-C5 humanized monoclonal antibody that inhibits the terminal complement pathway. Although transient improvement in kidney function was observed, both patients eventually experienced worsening renal parameters, with increasing proteinuria and hematuria, culminating in progression to end-stage kidney disease. Repeated kidney biopsies following eculizumab therapy demonstrated persistent, granular mesangial and capillary wall C3 (3+) staining on immunofluorescence studies, indicating ongoing complement activation upstream of the C5 blockade and the perpetuation of C3 deposits in the glomeruli. These cases underscore the limited efficacy of terminal complement inhibition in halting disease progression in C3GN.

C3 glomerulopathy (C3G) is a clinicopathologic entity characterized by glomerular inflammation with dominant staining for C3 on immunofluorescence microscopy. Electron microscopy is used to determine the location and type of deposits, which further divides C3G into C3 glomerulonephritis (C3GN) and dense deposit disease (DDD) based on ultrastructural findings. Both entities are progressive, with about 60% of patients progressing to end-stage kidney disease (ESKD) within 10 years. Recurrence after kidney transplantation occurs in up to 60% of C3G cases. New knowledge about the pathophysiology-different patterns of injury, histopathological scoring, apolipoprotein E staining, dysregulation of the alternative complement pathway (including both autoantibodies to and mutations in complement regulatory factors), as well as proteomic analyses-has allowed a better understanding of different pathophysiological profiles and clinical presentations, enabling individualized treatment. The role of nephroprotection is well established in C3G, as it is for other glomerular diseases. Non-specific treatment with corticosteroids and immunosuppression is associated with a variable response rate. However, more recently, results from clinical trials with proximal complement inhibitors have shown significant improvement in proteinuria and attenuation of the decline in estimated glomerular filtration rate (eGFR). Based on the results of these trials involving drugs that specifically target the upstream complement pathways, including the alternative pathway, new treatment options have recently become available for patients with C3G.