Glomerular Disease Research Articles

Prevalence of Kidney Complications in a Large Cohort of Patients with Recessive Dystrophic Epidermolysis Bullosa

Abstract Background Renal manifestations in patients with recessive dystrophic epidermolysis bullosa (RDEB) due to collagen VII deficiency have only been described in case series and could thus be underestimated. Objectives We aimed to describe the prevalence and types of kidney disease in a large cohort of patients with RDEB. Methods We conducted a retrospective study in two Parisian reference centers for RDEB and included patients with at least two concurrent blood and urine analyses. Kidney disease was defined as either glomerular with elevated albuminuria or tubulointerstitial with elevated β2-microglobulinuria. Results We included 120 patients with a confirmed molecular diagnosis of RDEB characterized by collagen VII deficiency between 2005 and 2021, of whom 36 (30%) exhibited kidney disease. Of these, 15 (12.5%) displayed glomerular disease, most commonly due to IgA nephropathy, and 21 (17.5%) presented with a tubulointerstitial presentation, often associated with complex hydroelectrolytic disorders. The immunohistochemistry study with anti-collagen VII antibody was positive on glomerular and tubular basement membranes in controls and negative in patients with complete collagen VII deficiency. In multivariate analysis, kidney disease was significantly associated with disease severity (p=0.002). Overall survival was reduced in RDEB patients with kidney complications. Based on these findings, we propose recommendations for the detection and monitoring of kidney disease in this patient population, with early referral to a nephrologist specifically upon the identification of renal abnormalities. Conclusions Kidney disease is common, correlates with disease severity, and impacts the prognosis of patients with RDEB. Systematic screening is recommended in this population.

Multimodal deep learning improving the accuracy of pathological diagnoses for membranous nephropathy

Objectives Renal biopsy is the gold standard for the diagnosis of glomerular diseases including membranous nephropathy (MN), however, it faces challenges in accuracy, objectivity, and reproducibility of tissue evaluation. This study aims to develop a multimodal pathological diagnosis system to assist pathologists in diagnosing MN in morphology. Methods Using PASM-stained, immunofluorescence, and electron microscopy images from MN patients, we built three deep-learning models to detect lesions. The outputs of these models were combined to provide a comprehensive pathological diagnosis. Our system was compared with pathologists, validated on external test sets, and detected in 138 patients with various kidney diseases. Results Considering PASM-stained images, our model had a classification accuracy of 91.74%, a recall of 81.97%, and an F1 score of 86.58% for spike identification. For immunofluorescence images, our model had an accuracy rate of 98.97%, a recall rate of 99.65%, and an F1 score of 99.31% for MN classification. Regarding the segmentation of electron-dense deposits, the segmentation model had a Dice coefficient of 85.66% and an IoU of 75.93%. Our model presented superior performance to that of pathologists in fluorescence image classification and segmentation of deposits, achieved high accuracy in spike identification and fluorescence image classification in external test sets, and could be targeted to diagnose MN in a wide range of glomerular diseases. Conclusions This multimodal pathological diagnosis system can not only assist pathologists in diagnosing MN rapidly and accurately but also lays the foundation to develop diagnostic models for other glomerular diseases.

Barriers to Patients Accessing Specialized Treatments for Glomerular Diseases.

Barriers to Patients Accessing Specialized Treatments for Glomerular Diseases.

Defining subgroups of pediatric nephrotic patients with urine proteomics

The molecular pathophysiology of nephrotic syndrome remains largely elusive in pediatric patients. While most children with minimal change disease (MCD) show favorable responses to immunosuppressive therapy, those with focal segmental glomerulosclerosis (FSGS) often exhibit poorer treatment responses, with many experiencing either partial remission or no remission of proteinuria. The need for reliable glomerular disease biomarkers to predict treatment response and understand molecular pathways governing responsiveness and resistance is a critical unmet need in pediatric nephrology. In this study, we sought to characterize urine proteomes in children with MCD and FSGS to identify biomarkers distinguishing disease activity and associated molecular pathways. Using quantitative proteomics, urine proteins from children with MCD and FSGS in the CureGN Study were identified and correlated with disease onset and activity. Unbiased cluster analyses of nephrotic urine proteomes demonstrated a cluster with relatively increased immune response and complement proteins, suggesting important distinctions in disease characteristics within the nephrotic subgroups. These analyses yielded patient subpopulations with proteinuria and distinct urine proteome differences associated with 116 proteins exerting cluster separation in the multivariate analyses. These findings highlight the potential of unsupervised clustering to identify disease subgroups and provide insights into the underlying molecular heterogeneity within nephrotic syndrome, paving the way for more tailored therapeutic strategies and improved patient management.

Clinical profile of children attending the pediatric nephrology outpatient clinic: a cross section study

BackgroundThe pattern of childhood kidney disease is variable and differs from one region to another. We aimed to identify the clinical profile of children attending the pediatric nephrology outpatient clinic. A cross section descriptive retrospective study was conducted including analysis of 365 patients’ files attended nephrology outpatient clinic over a period of 6 months.Results235 (64.4%) were males and 130 (35.6%) were females. Their mean age was 7 ± 3.6 years. 357 (97.8%) had isolated kidney disease and 8 (2.2%) had kidney involvement in systemic diseases. The commonest diseases in children with isolated kidney disease, were glomerular diseases (134 patients, 36.7%), followed by congenital anomalies of the kidney and urinary tract (CAKUT) (111 patients, 30.4%). Anemia was reported in 223 (61.1%) patients. Hypertension was reported in 175 (47.9%) patients while 156 (42.7%) patients had growth impairment. Patients with CAKUT had significantly higher incidence of anemia and growth impairment.ConclusionsAmong the study population, glomerular diseases and CAKUT were the commonest causes of kidney diseases. CAKUT are commonly associated with anemia and growth impairment. Close follow up of blood pressure, growth parameters and hemoglobin level is recommended with advanced stages of chronic kidney disease.

Protocol Biopsies in Kidney Transplant Recipients: Current Practice After Much Discussion

Protocol biopsies are a fundamental component in the management of kidney transplant recipients, offering critical insights into graft health by detecting subclinical pathological changes undetectable through routine clinical and laboratory assessments. Conducted at predetermined intervals, these biopsies enable early identification of subclinical rejection, chronic allograft nephropathy, drug-induced toxicities, viral infections such as BK polyomavirus nephropathy, and recurrence of primary glomerular diseases. Early detection facilitates timely therapeutic interventions, including immunosuppressive regimen adjustments, which are pivotal in preserving graft function and improving long-term outcomes. While the optimal timing and frequency of protocol biopsies vary, early post-transplant biopsies within the first year are widely advocated. High-risk groups, including ABO- and HLA-incompatible recipients and those with recurrent primary nephropathies, particularly benefit from surveillance biopsies. Despite the invasive nature and associated risks of biopsy procedures, most experts agree that the benefits outweigh the risks in selected populations. However, the role of routine protocol biopsies in low-risk patients remains debated due to unclear long-term outcome improvements and resource considerations. Retrospective observational studies have demonstrated the ability of protocol biopsies to detect subclinical pathological changes such as rejection, drug toxicity, viral infections, and recurrent diseases before clinical or laboratory abnormalities appear. These studies also highlight the impact of biopsy-guided interventions on graft survival and management in high-risk groups (e.g., HLA- and ABO-incompatible recipients, and patients at risk for disease recurrence). Furthermore, randomized controlled trials provide higher-level evidence showing that protocol biopsy-guided interventions improve graft function, reflected by better serum creatinine levels and glomerular filtration rates, compared to indicated biopsies alone. They also emphasize the importance of both early and late surveillance biopsies for predicting long-term outcomes. Expert opinion and consensus acknowledge the benefits of protocol biopsies for early detection and tailored management but also highlight ongoing debates regarding their routine use in low-risk patients due to risks, costs, and resource considerations. Overall, protocol biopsies represent a valuable tool for personalized graft monitoring and management, aiding in early detection of complications, guiding immunosuppressive therapy, and enhancing graft longevity. Further multicenter randomized trials are needed to refine guidelines and optimize their clinical utility.

Biofabrication of a Filtration Barrier by Integrating Electrospun Membranes and Flow in a Glomerular Co-Culture.

The glomerular filtration barrier (GFB), composed of glomerular endothelial cells, podocytes, and the glomerular basement membrane (GBM), is essential for selective filtration in the kidney. Damage to any GFB component results in proteinuria and kidney failure. To model glomerular pathophysiology and test therapies, this study introduces an ex vivo GFB model using electrospun poly-L-lactic acid fibers that mimic the GBM. The fibers are functionalized with polydopamine and gelatin, then seeded with human glomerular endothelial cells and podocytes on opposite sides. This biomimetic setup supports monolayer formation, cell-type-specific marker expression, and appropriate morphology of both cell types, including those derived from human induced pluripotent stem cells (hiPSCs). The model demonstrates bidirectional cell-cell communication across the membrane. Permeability assays confirm size-selective dextran filtration. Under flow conditions in a custom 3D-printed micro-bioreactor, endothelial cells develop fenestrae-like structures, whereas podocytes form foot process-like extension features, which are often lacking in static in vitro systems. This platform replicates critical features of the native GFB and provides a robust system for studying glomerular function, disease mechanisms, and therapeutic responses. Moreover, incorporating hiPSC-derived podocytes enables exploration of patient-specific mutations and personalized treatment strategies in kidney disease.

Epidemiology of glomerular diseases in a Colombian population.

Epidemiology of glomerular diseases in a Colombian population.

ANGPTL3 vital role in different kidney diseases. Current knowledge and future perspectives.

ANGPTL3 vital role in different kidney diseases. Current knowledge and future perspectives.

A Re-evaluation of Renal Biopsy-based Diagnoses Through a Genetic Analysis in Two Families with Alport Syndrome: Case Reports

Alport syndrome is an inherited disorder characterized by progressive renal failure, sensorineural hearing loss, and ocular involvement due to pathogenic variants of genes encoding type IV collagen. A renal biopsy does not reveal specific findings in the early stages; thus, Alport syndrome may be diagnosed as another glomerular disease. We herein report two families that were previously diagnosed with other glomerular diseases based on renal biopsies and were then accurately diagnosed by genetic testing. An early diagnosis may lead to the avoidance of unnecessary biopsies and treatments, and appropriate management may improve the renal prognosis.

Ferroptosis-related gene DUSP1 improves renal fibrosis in immunoglobulin A nephropathy through regulating p38 MAPK/Nrf2-induced ferroptosis

Background Immunoglobulin A nephropathy (IgAN) is a common primary glomerular disease linked to ferroptosis. We aimed to identify key ferroptosis-related genes in IgAN and clarify their mechanism. Methods Based on the data from GEO, FerrDb, Genecards, and previous publications, differential expression analysis, Machine learning (LASSO and SVM-RFE), and Weighted correlation network Analysis were exploited to screen the ferroptosis-related genes in IgAN. Furthermore, immune infiltration analysis, GSEA, and receiver operator characteristic curve were performed to identify the key genes and evaluate their diagnostic ability. A TGF-β1-induced HK-2 cell model of fibrosis with oe-DUSP1 transfection and treatment with the p38 MAPK activator U-46619 was used to validate the findings. Results We identified 23 ferroptosis-related differential expressed genes in IgAN, enriched in ECM-receptor interaction, focal adhesion, and allograft rejection. Four genes (CDO1, NR4A1, JUN, DUSP1) exhibited promising diagnostic value in IgAN (AUC > 0.90). NR4A1 and DUSP1 were down-regulated in IgAN and correlated with immune cell infiltration like Eosinophil, immature B cell, and activated B cell. DUSP1 overexpression inactivated p38 MAPK, increased Nrf2 and ferroptosis markers (GPX4 and SLC7A11), decreased Fe 2+ and fibrosis. U-46619 addition had no effects on DUSP1, but reversed above alterations. Conclusions NR4A1 and DUSP1 are key diagnostic markers in IgAN, with DUSP1 modulating fibrosis via p38 MAPK/Nrf2-mediated ferroptosis.

Targeting the Roots of Kidney Disease: Systematic Review of the Therapies Targeting the Complement System

Background/Objectives: The field of nephrology is increasingly embracing advanced treatments and clinical trials that focus on inhibiting specific components of the complement cascade, a key driver in complement-mediated kidney diseases. Materials and Methods: This review aims to summarize innovative therapies targeting various pathways, including the inhibition of the terminal part of the complement pathway (mainly C5), the alternative pathway (factor B inhibitors), and the lectin pathway (MASP inhibitors. C5 inhibitors play a critical role in preventing the formation of the membrane attack complex (MAC), offering effective solutions for conditions like atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria (PNH). Meanwhile, avacopan, a C5a receptor antagonist, addresses ANCA-associated vasculitis (AAV) by mitigating inflammation and enabling reduced reliance on corticosteroids. Similarly, narsoplimab, which inhibits MASP-2, targets the lectin pathway implicated in conditions such as aHUS. Iptacopan, a factor B inhibitor, focuses on the alternative pathway and demonstrates efficacy in managing C3 glomerulopathy (C3G). Results: A systematic review of complement-targeted therapies was conducted, analysing studies from 2013 to 2023 that address unmet medical needs in primary and secondary glomerular diseases. Conclusions: Our systematic review of complement-targeted therapies shows that these tailored and innovative treatments may specifically address unmet medical needs in primary and secondary glomerular diseases.

Hidden in the Absence: Clinicopathologic Insights on Kidney Diseases Associated With Selective IgA Deficiency.

Hidden in the Absence: Clinicopathologic Insights on Kidney Diseases Associated With Selective IgA Deficiency.

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of HSK39297 in Chinese Healthy Subjects: A Phase 1 Clinical Trial.

HSK39297 is a novel complement factor B inhibitor, and this phase 1 trial was designed to assess its pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability in healthy Chinese subjects. This study included 46 subjects in the single ascending dose (SAD) part (50-600 mg) and 50 subjects in the multiple ascending dose (MAD) part (50-125 mg BID and 200-300 mg QD). Among them, a food effect study was conducted in the SAD 200 mg group. Adverse events (AEs) reported after the initial dose of the study drug were considered treatment-emergent AEs (TEAEs). Blood samples were collected to measure plasma concentrations of HSK39297 at predefined time points and analyzed at a centralized laboratory. In addition, PD analysis was conducted by measuring complement alternative pathway (AP) activity and Bb concentrations. According to the results, we found single and multiple doses of HSK39297 were safe and well tolerated in all subjects. Within SAD of 50-600 mg dose range, the Cmax, AUC0-t, and AUC0-∞ exhibited nonlinear PK characteristics. The high-fat meals did not significantly affect the absorption rate and systemic exposure levels of HSK39297, and GMRs for fed versus fasting states were 108.05% (99.66%, 117.15%), 98.73% (89.34%, 109.09%), and 97.86% (84.66%, 113.11%), respectively. In MAD part, dose-drug exposure showed a linear relationship. PD analysis indicated that oral administration of HSK39297 tablets resulted in dose-dependent inhibition of the AP activity and Bb concentration. These findings support advancing HSK39297 into later-phase trials for complement-mediated glomerular diseases.

How I Treat Glomerular Diseases in Older Adults.

How I Treat Glomerular Diseases in Older Adults.

Frequency, Risk Factors, and Outcome of Acute Kidney Injury in Idiopathic Childhood Nephrotic Syndrome: A Systematic Review

Background and Objectives: Idiopathic nephrotic syndrome is a common glomerular disease with a good prognosis in the long term. However, the development of acute kidney injury may complicate the disease course. This systematic review was conducted to evaluate the frequency, risk factors and outcome of AKI in children with idiopathic nephrotic syndrome. Methods: PubMed, EMBASE, and CENTRAL were systematically searched from January 1974 to July 2024 for retrospective and prospective observational studies. The systematic review was prospectively registered with PROSPERO and written in compliance with PRISMA guidelines. The quality assessment tool was used to evaluate the quality of included studies. Results: Out of 271 identified studies, 14 were included in the systematic review. Most studies were retrospective in design. The most common risk factors for acute kidney injury in children were infections (sepsis, spontaneous bacterial peritonitis, pneumonia, and urinary tract infections) and nephrotoxic drug exposure (e.g., nephrotoxic antibiotics, renin-angiotensin modifiers, methylprednisolone, and calcineurin inhibitors). Recovery from AKI occurred in 48–100% of cases, while chronic kidney disease development ranged from 0 - 41.2% and a maximum reported mortality rate of 23%. The quality assessment through NHLBI rated 85% studies as good. Conclusion: Acute kidney injury is a relatively frequent and serious complication in children with nephrotic syndrome, often associated with infections and nephrotoxic drug exposure. This systematic review, conducted using a structured approach highlights the need of preventive strategies and further research in this vulnerable population.

Pharmacokinetic Characterization of Rituximab in Patients with Glomerular Diseases.

Rituximab is commonly used to treat patients with primary glomerular diseases; however, its pharmacokinetics in this population have not been fully described yet. This single-center, open-label, uncontrolled clinical trial included adult patients with glomerular diseases who required rituximab treatment (NEFRTX; EudraCT: 2020-000484-23). Patients received 1 or 0.5 g of rituximab on day 1 (and d14 in some cases). Blood and urine samples were collected at days 1, 7, 14, 28, and 45 to measure biochemical parameters (proteinuria, albuminemia, plasma immunoglobulin, and urine immunoglobulin), rituximab, and antidrug antibody concentrations. The gene encoding the neonatal fragment-crystallizable receptor was also characterized. Linear regression and Win-Nonlin 1.1 were used for pharmacokinetic analysis. Thirty-five cases (30 patients) were included in this study. Pharmacokinetic parameters were expressed as mean (SD): maximum plasma concentration, 179.4 (71.8) mcg/mL; volume of distribution, 78.9 (31.4) mL/kg; clearance, 0.30 (0.27) mL/h/kg; half-life (t1/2), 11.6 (5.8) d; elimination rate constant, 0.0036 (0.0030) hour-1; and area under the curve, 117,756.1 (88,228.1) mcg·h/mL. Antidrug antibody was detected on d1 in 3 cases (8.6%) and was negative by d28.Rituximab t1/2 was represented by the formula: t1/2 = A-B·Log (Proteinuria)+C·Albuminemia, where A = 515.1 (128.8-901.3), B = 182.1 (-108.6 to -35.4), and C = 39.5 (-10.9 to 89.9).There were significant differences in rituximab t1/2 based on diagnosis (P = 0.025), early treatment (P = 0.008), proteinuria >2.4g/24h (P < 0.001), plasma immunoglobulin <650 mg/dL (P = 0.048), and detectable urine immunoglobulin (P = 0.018). Albuminemia and proteinuria affect rituximab t1/2 and drug exposure in patients with glomerular diseases. Patients with proteinuria >2.4g/24h may require higher frequent dosing for adequate rituximab exposure. Establishing an optimal dosing regimen in this population remains warranted.

The differential expression of MAGI2 in glomerulopathies and its application as a molecular discriminator of podocytopathies

BackgroundPodocyte dysfunction is central to various glomerular diseases, necessitating reliable biomarkers for early detection and diagnosis. This study investigates the regulatory mechanisms of membrane-associated guanylate kinase inverted 2 (MAGI2) and its potential as a biomarker for podocytopathies.MethodsUsing fluorescence confocal laser scanning microscopy and super-resolution structured illumination microscopy of immunostained tissue sections of murine, human, and zebrafish tissue we investigated the subcellular location of MAGI2 in the kidney. We assessed the differential regulation of MAGI2 in glomerular disease animal models, and isolated glomerular dedifferentiation using immunostainings and LC–MS/MS tandem mass spectrometry. With CRISPR-Cas9, we generated zebrafish F0 generation mutants lacking either the zebrafish orthologue magi2a or nphs1.ResultsThe expression of the gene coding for the scaffolding protein MAGI2 was examined across four species and demonstrated to be conserved within the podocyte filtration slit. In vitro and in vivo studies using isolated glomeruli and mammalian animal models of glomerular disease, including DOCA-salt hypertension, nephrotoxic serum nephritis, and puromycin aminonucleoside nephropathy, demonstrated significant downregulation of MAGI2 in injured podocytes. This downregulation was also conserved in a zebrafish model of focal and segmental glomerulosclerosis (FSGS), and the podocyte-specific MAGI2 ortholog Magi2a was reduced post podocyte injury. CRISPR/Cas9-generated zebrafish mutants for magi2a exhibited marked glomerular filtration barrier defects and downregulation of nephrin, underscoring MAGI2's critical role in podocyte function. Human biopsy analyses revealed differential MAGI2 expression: it was increased in minimal change disease (MCD) patients but significantly decreased in primary, but not secondary FSGS cases. As MAGI2 localization did not change in disease states it is an alternative marker for super-resolution microscopy-based morphometry of the filtration slit, correlating with nephrin-based measurements.ConclusionsThese findings highlight the potential of MAGI2 as a sensitive biomarker for podocyte injury and its diagnostic utility as a molecular discriminator in differentiating between primary FSGS and MCD in kidney biopsies.

Podocyte YAP and TAZ hyperactivation drives glomerular epithelial proliferative diseases in mice and humans.

Kidney diseases characterized by glomerular epithelial cell proliferation are rare but often devastating, frequently leading to progressive scarring and renal failure. Ranging from autoimmune-induced crescentic glomerulonephritis to HIV infection-induced collapsing glomerulopathy, these diseases are triggered by a wide variety of insults and have generally been thought of as different entities. Here, using immunostaining and spatial transcriptomics, we profiled human kidney biopsies collected from patients with two of these diseases, collapsing glomerulopathy and antineutrophil cytoplasmic antibody (ANCA) vasculitis-induced crescentic glomerulonephritis, to identify common disease-causing molecules. Although triggered by different insults, we identified abnormal hyperactivation of the transcription cofactors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in podocytes as a potential common driver of these diseases. To test this hypothesis, we genetically activated podocyte YAP and TAZ in cultured human cells and in mice by deleting the YAP and TAZ inhibitory large tumor suppressor kinases (LATSs). LATS deficiency in mouse podocytes induced a phenotypic transition in vitro, characterized by a highly distorted structure and an increase in matrix gene expression, mimicking many features of the podocytopathy seen in diseases characterized by glomerular epithelial proliferation. In mice, LATS-deficient podocytes orchestrated a profibrotic and pro-proliferative response in surrounding glomerular cells, a characteristic phenomenon of glomerular epithelial proliferative diseases. This response was attenuated when we also deleted podocyte YAP or TAZ in these mice. Together, our findings point to podocyte YAP-TAZ hyperactivation as a previously unrecognized and unifying driver of glomerular epithelial proliferative diseases.

Exploring causality between peripheral blood B cell subtypes and membranous nephropathy: A two-sample Mendelian randomization study

IntroductionMembranous nephropathy (MN) is a glomerular autoimmune disease associated with nephrotic syndrome. This study explored the influence of peripheral blood B cell subtypes on MN using Mendelian randomization (MR).Material and methodsData on single-nucleotide polymorphisms (SNPs) associated with peripheral blood B cells and MN were obtained from a genome-wide association study (GWAS). Analytical methods included instrumental variable weighted (IVW), weighted median, weighted mode methods, and MR-Egger regression. Sensitivity analyses were conducted using MR-Egger, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) for outlier detection, Cochran’s Q test for heterogeneity, and leave-one-out analysis to assess the robustness of the findings.ResultsHigher levels of IgD+ CD24-B cell absolute count (OR 0.8285, 95% CI 0.7317-0.9381, P=0.003), B-cell activating factor receptor (BAFF-R) on IgD+ CD24-B cells (OR 0.9045, 95% CI 0.8275-0.9886, P=0.0269), BAFF-R on IgD+ CD38dim B cells (OR 0.9057, 95% CI 0.8277-0.991, P=0.0311), BAFF-R on IgD- CD27-B cells (OR 0.9134, 95% CI 0.8404-0.9928, P=0.0332), CD19 on IgD-CD24-B cells (OR 0.884, 95% CI 0.7906-0.9886, P=0.0306), CD24 on switched memory B cells (OR 0.8927, 95% CI 0.8133-0.9798, P=0.0169), and CD25 on switched memory B cells (OR 0.8768, 95% CI 0.7745-0.9927, P=0.0379) were strongly associated with an decreased risk of membranous nephropathy. Sensitivity analyses were conducted to confirm the stability of the findings.ConclusionsThis MR study supports the possibility of a genetic causal association between peripheral blood B cell subtypes and MN. The results enhance the comprehension of the immunological basis of MN and may play a role in personalized medicine.