Pub Date : 2026-01-01DOI: 10.1016/j.kint.2025.10.005
Menno Pruijm , Nicolas Belmar , Petter Bjornstad , David Z.I. Cherney , Vivek Das , Thomas Gunnarsson , Jeffrey B. Hodgin , Philip A. Schytz , Katherine R. Tuttle , Matthias Kretzler
Chronic kidney disease poses a major global health burden and is one of the most common complications of type 2 diabetes. Drug trials have demonstrated that treatments, including sodium-glucose cotransporter-2 inhibitors, a glucagon-like peptide-1 receptor agonist, and a nonsteroidal mineralocorticoid receptor antagonist, mitigate chronic kidney disease progression, but the underlying nephroprotective mechanisms of action remain incompletely understood, partly ascribed to their pleiotropic actions. New innovative trial designs are needed to tackle simultaneously the hemodynamic and structural effects induced by these drugs. The REMODEL trial (REnal MODE of action of semagLutide in patients with type 2 diabetes and chronic kidney disease; ClinicalTrials.gov identifier: NCT04865770) is designed to explore the mechanisms of action of semaglutide with a novel multiparametric approach, integrating functional magnetic resonance imaging and research kidney biopsies for structural and molecular interrogation and blood and urine biomarker analysis. Better understanding of these mechanisms will help explain semaglutide's beneficial effects on kidney disease outcomes, reported in the FLOW (Evaluate Renal Function with Semaglutide Once Weekly; ClinicalTrials.gov identifier: NCT03819153) trial, and may identify patient subpopulations to optimize treatment strategies. By combining diverse and state-of-the-art methods, REMODEL aims to pave the way to a larger use of mechanism of action trials in the near future. To this purpose, this article describes the REMODEL framework, methods, technical challenges, and lessons learned as a platform for future mechanistic trials of chronic kidney disease therapies and beyond.
{"title":"REMODELing mechanistic trials for kidney disease: a multimodal, tissue-centered approach to understand the renal mechanism of action of semaglutide","authors":"Menno Pruijm , Nicolas Belmar , Petter Bjornstad , David Z.I. Cherney , Vivek Das , Thomas Gunnarsson , Jeffrey B. Hodgin , Philip A. Schytz , Katherine R. Tuttle , Matthias Kretzler","doi":"10.1016/j.kint.2025.10.005","DOIUrl":"10.1016/j.kint.2025.10.005","url":null,"abstract":"<div><div>Chronic kidney disease poses a major global health burden and is one of the most common complications of type 2 diabetes. Drug trials have demonstrated that treatments, including sodium-glucose cotransporter-2 inhibitors, a glucagon-like peptide-1 receptor agonist, and a nonsteroidal mineralocorticoid receptor antagonist, mitigate chronic kidney disease progression, but the underlying nephroprotective mechanisms of action remain incompletely understood, partly ascribed to their pleiotropic actions. New innovative trial designs are needed to tackle simultaneously the hemodynamic and structural effects induced by these drugs. The REMODEL trial (REnal MODE of action of semagLutide in patients with type 2 diabetes and chronic kidney disease; ClinicalTrials.gov identifier: NCT04865770) is designed to explore the mechanisms of action of semaglutide with a novel multiparametric approach, integrating functional magnetic resonance imaging and research kidney biopsies for structural and molecular interrogation and blood and urine biomarker analysis. Better understanding of these mechanisms will help explain semaglutide's beneficial effects on kidney disease outcomes, reported in the FLOW (Evaluate Renal Function with Semaglutide Once Weekly; ClinicalTrials.gov identifier: NCT03819153) trial, and may identify patient subpopulations to optimize treatment strategies. By combining diverse and state-of-the-art methods, REMODEL aims to pave the way to a larger use of mechanism of action trials in the near future. To this purpose, this article describes the REMODEL framework, methods, technical challenges, and lessons learned as a platform for future mechanistic trials of chronic kidney disease therapies and beyond.</div></div>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages 6-16"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145461316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.kint.2025.08.024
Laisel Martinez , Filipe F. Stoyell-Conti , Marwan Tabbara , Miguel G. Rojas , Simone Pereira-Simon , Nieves Santos Falcon , Reyniel Hernandez Lopez , Daniella Galtes , Christina Kosanovic , Anthony J. Griswold , Xiaofeng Yang , Yan-Ting Shiu , Timmy Lee , Juan C. Duque , Marco A. Ladino , Loay H. Salman , Xiaochun Long , Roberto I. Vazquez-Padron
Introduction
The biological mechanisms underlying arteriovenous fistula (AVF) maturation in patients receiving hemodialysis remain poorly understood despite decades of research.
Methods
To address this gap, we first investigated the cellular changes in the venous wall after fistula creation in histological biopsies of longitudinal veins and AVF samples (23 patients). Using single-cell RNA sequencing of 70,281 cells from independent pre-access veins, early resections, mature, and failed AVFs (20 patients), we then created a complementary transcriptomic atlas of the human vein before and after anastomosis.
Results
AVFs had increased wall area and cell number but reduced cell density in histological sections, suggesting that postoperative wall thickening occurs predominantly through extracellular matrix (ECM) deposition. The early remodeling of the AVF was characterized by a loss of smooth muscle cells, increased monocyte infiltration, and the reprograming of myofibroblasts and fibroblasts toward reparative phenotypes. In contrast, later stages of remodeling were dominated by ECM-producing myofibroblasts and fibroblasts, occurring in the context of low cell proliferation. Failed AVFs displayed persistent inflammation and exaggerated healing responses as defining features. Specifically, these AVFs contained abundant proinflammatory and adhesive macrophages with upregulation of the Myddosome signaling complex, proinflammatory vasa vasorum endothelial cells, and hyperactivated fibroblasts and myofibroblasts. Macrophage-derived osteopontin emerged as a key paracrine signal driving vascular cell activation in failed AVFs. Additional signals derived from fibroblasts, myofibroblasts, and endothelial cells, including chemokines, semaphorins, fibroblast growth factors, angiopoietin-like proteins, periostin, and transforming growth factor-β, were also enriched within the inflammatory microenvironment sustaining AVF failure.
Conclusions
Our findings uncover previously unrecognized cellular and molecular patterns in human veins following AVF creation, providing novel insights and potential therapeutic targets to improve AVF maturation outcomes.
{"title":"The single-cell landscape of the human vein after arteriovenous fistula creation and implications for maturation failure","authors":"Laisel Martinez , Filipe F. Stoyell-Conti , Marwan Tabbara , Miguel G. Rojas , Simone Pereira-Simon , Nieves Santos Falcon , Reyniel Hernandez Lopez , Daniella Galtes , Christina Kosanovic , Anthony J. Griswold , Xiaofeng Yang , Yan-Ting Shiu , Timmy Lee , Juan C. Duque , Marco A. Ladino , Loay H. Salman , Xiaochun Long , Roberto I. Vazquez-Padron","doi":"10.1016/j.kint.2025.08.024","DOIUrl":"10.1016/j.kint.2025.08.024","url":null,"abstract":"<div><h3>Introduction</h3><div>The biological mechanisms underlying arteriovenous fistula (AVF) maturation in patients receiving hemodialysis remain poorly understood despite decades of research.</div></div><div><h3>Methods</h3><div>To address this gap, we first investigated the cellular changes in the venous wall after fistula creation in histological biopsies of longitudinal veins and AVF samples (23 patients). Using single-cell RNA sequencing of 70,281 cells from independent pre-access veins, early resections, mature, and failed AVFs (20 patients), we then created a complementary transcriptomic atlas of the human vein before and after anastomosis.</div></div><div><h3>Results</h3><div>AVFs had increased wall area and cell number but reduced cell density in histological sections, suggesting that postoperative wall thickening occurs predominantly through extracellular matrix (ECM) deposition. The early remodeling of the AVF was characterized by a loss of smooth muscle cells, increased monocyte infiltration, and the reprograming of myofibroblasts and fibroblasts toward reparative phenotypes. In contrast, later stages of remodeling were dominated by ECM-producing myofibroblasts and fibroblasts, occurring in the context of low cell proliferation. Failed AVFs displayed persistent inflammation and exaggerated healing responses as defining features. Specifically, these AVFs contained abundant proinflammatory and adhesive macrophages with upregulation of the Myddosome signaling complex, proinflammatory vasa vasorum endothelial cells, and hyperactivated fibroblasts and myofibroblasts. Macrophage-derived osteopontin emerged as a key paracrine signal driving vascular cell activation in failed AVFs. Additional signals derived from fibroblasts, myofibroblasts, and endothelial cells, including chemokines, semaphorins, fibroblast growth factors, angiopoietin-like proteins, periostin, and transforming growth factor-β, were also enriched within the inflammatory microenvironment sustaining AVF failure.</div></div><div><h3>Conclusions</h3><div>Our findings uncover previously unrecognized cellular and molecular patterns in human veins following AVF creation, providing novel insights and potential therapeutic targets to improve AVF maturation outcomes.</div></div>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages 160-177"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.kint.2025.08.041
Gabriel Morin , Pierre Isnard , Guillaume Canaud
Phosphoinositide 3-kinase α (PI3Kα) is a ubiquitous lipid kinase that transduces extracellular growth, proliferation, and metabolism signals. Genes involved in the PI3Kα signaling pathway are frequently mutated in cancer. Apart from malignant conditions, monogenic rare disorders, called PIK3CA-related overgrowth syndromes, are also caused by mosaic mutations in PIK3CA, the gene encoding the catalytic subunit of PI3Kα, resulting in increased signaling promoting abnormal growth and proliferation. Recent studies have shown that alpelisib, a PI3Kα inhibitor initially designed for breast cancer, is also effective at treating PIK3CA-related overgrowth syndrome. Linking rare malformation syndromes and kidney disease, the improvement of kidney function following treatment with alpelisib in a patient with PIK3CA-related overgrowth syndrome with nonspecific glomerular lesions shed light on the involvement of PI3Kα across various nephropathies. Moreover, the identification of a PIK3CA mosaic variant in his glomerular epithelial cells suggested that mosaic variants of the PI3Kα pathway might explain cases of chronic kidney disease of undetermined etiology. Finally, the deleterious role of the PI3Kα pathway also extends to a wide variety of kidney diseases, such as lupus nephritis, diabetes, or autosomal dominant polycystic kidney disease. In unrelated disorders, PI3Kα involvement has been reported in various cell types, such as mesangial, tubular, and immune cells. This review aims at summarizing the available evidence on the involvement of the pathway in monogenic disorders and kidney disease, highlighting PI3Kα as a potential novel therapeutic target in various nephropathies.
{"title":"Drug repurposing in PIK3CA-related overgrowth spectrum: breakthroughs from overgrowth syndromes to kidney disease","authors":"Gabriel Morin , Pierre Isnard , Guillaume Canaud","doi":"10.1016/j.kint.2025.08.041","DOIUrl":"10.1016/j.kint.2025.08.041","url":null,"abstract":"<div><div>Phosphoinositide 3-kinase α (PI3Kα) is a ubiquitous lipid kinase that transduces extracellular growth, proliferation, and metabolism signals. Genes involved in the PI3Kα signaling pathway are frequently mutated in cancer. Apart from malignant conditions, monogenic rare disorders, called <em>PIK3CA</em>-related overgrowth syndromes, are also caused by mosaic mutations in <em>PIK3CA</em>, the gene encoding the catalytic subunit of PI3Kα, resulting in increased signaling promoting abnormal growth and proliferation. Recent studies have shown that alpelisib, a PI3Kα inhibitor initially designed for breast cancer, is also effective at treating <em>PIK3CA</em>-related overgrowth syndrome. Linking rare malformation syndromes and kidney disease, the improvement of kidney function following treatment with alpelisib in a patient with <em>PIK3CA</em>-related overgrowth syndrome with nonspecific glomerular lesions shed light on the involvement of PI3Kα across various nephropathies. Moreover, the identification of a <em>PIK3CA</em> mosaic variant in his glomerular epithelial cells suggested that mosaic variants of the PI3Kα pathway might explain cases of chronic kidney disease of undetermined etiology. Finally, the deleterious role of the PI3Kα pathway also extends to a wide variety of kidney diseases, such as lupus nephritis, diabetes, or autosomal dominant polycystic kidney disease. In unrelated disorders, PI3Kα involvement has been reported in various cell types, such as mesangial, tubular, and immune cells. This review aims at summarizing the available evidence on the involvement of the pathway in monogenic disorders and kidney disease, highlighting PI3Kα as a potential novel therapeutic target in various nephropathies.</div></div>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages 64-72"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145382744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.kint.2025.09.026
Jordi Vilardell-Vilà , Conxita Jacobs-Cachá , Nerea Martos-Guillamí , Aku Enam Motto , Carmen Llorens-Cebrià , Maciej Lech , Irene Martínez-Díaz , Javier Esparcia-Estrela , Marc Patricio-Liébana , Sheila Bermejo , Roser Ferrer-Costa , Juan Leon-Roman , Hans-Joachim Anders , Maria José Soler
Introduction
Sodium glucose cotransporter 2 inhibitors (SGT2i) have delayed the progression of chronic kidney disease with or without diabetes. However, its effect in active glomerulonephritis such as lupus nephritis (LN) is unknown. Here, we tested the effect of the SGLT2i empagliflozin (EMP) in MRLlpr/lpr mice, a model of spontaneous systemic lupus erythematosus with active LN.
Methods
Female MRLIpr/lpr mice were treated with 10 mg/kg/day of the EMP for four weeks. To better mimic the patient setting, MRLIpr/lpr mice were randomly assigned to EMP or untreated control group between weeks nine and 13 once the signs of active LN appeared. Proteinuria levels over 100 mg/dl (++ in reactive strips) or lymphadenopathy in minimum two bilateral sites (cervical, branchial or inguinal) with proteinuria over 30mg/dl were considered as signs of an active LN. Lymphadenopathy, body weight, water and food intake were monitored weekly. Blood glucose was measured bi-weekly, while glomerular filtration rate and albumin-to-creatinine ratio were obtained at the beginning and at the end of the experiment.
Results
EMP treatment increased glycosuria and water intake in MRLlpr/lpr mice, but did not affect blood glucose levels, body weight, or food intake. After four weeks of treatment, EMP did not alter glomerular filtration rate, albuminuria, histological glomerular IgG deposits, activity or chronicity indexes of LN, or interstitial fibrosis in MRLlpr/lpr mice.
Conclusions
Our results indicate that EMP does not affect proteinuria or kidney excretory function nor signs of lupus in MRLlpr/lpr mice with active LN. This suggests that SGLT2i may not affect LN activity, and they should be, rather, considered to target the chronic kidney disease aspect of LN to prevent further nephron loss.
{"title":"Sodium glucose cotransporter 2 inhibition does not improve active lupus nephritis in MRLlpr/lpr mice","authors":"Jordi Vilardell-Vilà , Conxita Jacobs-Cachá , Nerea Martos-Guillamí , Aku Enam Motto , Carmen Llorens-Cebrià , Maciej Lech , Irene Martínez-Díaz , Javier Esparcia-Estrela , Marc Patricio-Liébana , Sheila Bermejo , Roser Ferrer-Costa , Juan Leon-Roman , Hans-Joachim Anders , Maria José Soler","doi":"10.1016/j.kint.2025.09.026","DOIUrl":"10.1016/j.kint.2025.09.026","url":null,"abstract":"<div><h3>Introduction</h3><div>Sodium glucose cotransporter 2 inhibitors (SGT2i) have delayed the progression of chronic kidney disease with or without diabetes. However, its effect in active glomerulonephritis such as lupus nephritis (LN) is unknown. Here, we tested the effect of the SGLT2i empagliflozin (EMP) in MRLlpr/lpr mice, a model of spontaneous systemic lupus erythematosus with active LN.</div></div><div><h3>Methods</h3><div>Female MRLIpr/lpr mice were treated with 10 mg/kg/day of the EMP for four weeks. To better mimic the patient setting, MRLIpr/lpr mice were randomly assigned to EMP or untreated control group between weeks nine and 13 once the signs of active LN appeared. Proteinuria levels over 100 mg/dl (++ in reactive strips) or lymphadenopathy in minimum two bilateral sites (cervical, branchial or inguinal) with proteinuria over 30mg/dl were considered as signs of an active LN. Lymphadenopathy, body weight, water and food intake were monitored weekly. Blood glucose was measured bi-weekly, while glomerular filtration rate and albumin-to-creatinine ratio were obtained at the beginning and at the end of the experiment.</div></div><div><h3>Results</h3><div>EMP treatment increased glycosuria and water intake in MRLlpr/lpr mice, but did not affect blood glucose levels, body weight, or food intake. After four weeks of treatment, EMP did not alter glomerular filtration rate, albuminuria, histological glomerular IgG deposits, activity or chronicity indexes of LN, or interstitial fibrosis in MRLlpr/lpr mice.</div></div><div><h3>Conclusions</h3><div>Our results indicate that EMP does not affect proteinuria or kidney excretory function nor signs of lupus in MRLlpr/lpr mice with active LN. This suggests that SGLT2i may not affect LN activity, and they should be, rather, considered to target the chronic kidney disease aspect of LN to prevent further nephron loss.</div></div>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages 211-216"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145397086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.kint.2025.06.006
{"title":"KDIGO 2026 Clinical Practice Guideline for the Management of Anemia in Chronic Kidney Disease (CKD)","authors":"","doi":"10.1016/j.kint.2025.06.006","DOIUrl":"10.1016/j.kint.2025.06.006","url":null,"abstract":"","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages S1-S99"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145880228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.kint.2025.10.007
Nicola M. Tomas
Membranous nephropathy is an autoimmune disease most commonly caused by autoantibodies against the phospholipase A2 receptor 1. The pathogenicity of these autoantibodies offers the chance to develop highly specific therapies by targeting their cellular source (i.e., the autoreactive B cells). In this issue, Altun et al. provide further evidence for the feasibility of chimeric autoantibody receptor T cells to selectively eliminate these cells in phospholipase A2 receptor 1–associated membranous nephropathy, offering unprecedented specificity. Future studies need to address important open questions to evaluate the translational potential of this approach.
{"title":"Toward precision immunotherapy in nephrology: 1 step forward","authors":"Nicola M. Tomas","doi":"10.1016/j.kint.2025.10.007","DOIUrl":"10.1016/j.kint.2025.10.007","url":null,"abstract":"<div><div>Membranous nephropathy is an autoimmune disease most commonly caused by autoantibodies against the phospholipase A2 receptor 1. The pathogenicity of these autoantibodies offers the chance to develop highly specific therapies by targeting their cellular source (i.e., the autoreactive B cells). In this issue, Altun <em>et al.</em> provide further evidence for the feasibility of chimeric autoantibody receptor T cells to selectively eliminate these cells in phospholipase A2 receptor 1–associated membranous nephropathy, offering unprecedented specificity. Future studies need to address important open questions to evaluate the translational potential of this approach.</div></div>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages 31-33"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145883406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.kint.2025.07.017
Griffith B. Perkins , P. Toby Coates , Robert L. Fairchild
{"title":"Out of chaos, comes tolerance: targeting the T cells driving antibody-mediated rejection","authors":"Griffith B. Perkins , P. Toby Coates , Robert L. Fairchild","doi":"10.1016/j.kint.2025.07.017","DOIUrl":"10.1016/j.kint.2025.07.017","url":null,"abstract":"","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages 27-30"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.kint.2025.10.006
Samih H. Nasr , Tiffany N. Caza , Christopher P. Larsen , Aaron Storey , Alessia Buglioni , Mariam Priya Alexander , Mary E. Fidler , Lihong Bu , Lynn D. Cornell , Fernando C. Fervenza , Sanjeev Sethi
Introduction
Most newly discovered membranous nephropathy (MN) antigens have been mutually exclusive, but there are rare cases of dual antigen MN based on immunohistochemistry (IHC)/immunofluorescence (IF) or serologic testing. Here, we searched for cases of dual antigen MN at Mayo Clinic and Arkana Laboratories with the diagnosis established by light/electron microscopy and IF.
Methods
At Mayo Clinic, we performed laser capture microdissection of glomeruli followed by liquid chromatography tandem mass spectrometry (LC MS/MS) on paraffin-embedded kidney biopsy tissue to detect 12 MN antigens.
Results
Nine cases of dual antigen MN (four at Mayo Clinic, five at Arkana Laboratories) were confirmed by both LC MS/MS and IHC/IF. The detected antigens were NELL1 + CNTN1 (two cases), NCAM1 + EXT1/2 (two cases), and one case each NDNF + NELL1, NELL1 + PLA2R1, THSD7A + PLA2R1, PCDH7 + PLA2R1, and CNTN1 + PCDH7. Median age at diagnosis was 68 years (range 23-84). Eight patients presented with nephrotic syndrome and microscopic hematuria. Median serum creatinine at diagnosis was 1 mg/dL. The underlying conditions, when present, and serological characteristics, correlated with the involved antigens. The frequency at Mayo Clinic was 2.6% of PLA2R1-negative MN cases.
Conclusions
Given that IHC/IF and LC MS/MS for MN antigen detection are typically not pursued in PLA2R1-associated MN, dual-antigen MN is likely underdiagnosed. Dual-antigen MN can involve a variety of MN antigens, including those that are podocyte-expressed, transmembrane, or secreted. Most patients with MN present with nephrotic syndrome and microscopic hematuria. Further studies are needed to understand the pathophysiology of dual-antigen MN and determine their role both in the therapeutic approach and clinical outcomes. Our findings suggest that LC MS/MS is a valuable methodology for detection of dual antigen MN.
{"title":"Dual-antigen membranous nephropathy","authors":"Samih H. Nasr , Tiffany N. Caza , Christopher P. Larsen , Aaron Storey , Alessia Buglioni , Mariam Priya Alexander , Mary E. Fidler , Lihong Bu , Lynn D. Cornell , Fernando C. Fervenza , Sanjeev Sethi","doi":"10.1016/j.kint.2025.10.006","DOIUrl":"10.1016/j.kint.2025.10.006","url":null,"abstract":"<div><h3>Introduction</h3><div>Most newly discovered membranous nephropathy (MN) antigens have been mutually exclusive, but there are rare cases of dual antigen MN based on immunohistochemistry (IHC)/immunofluorescence (IF) or serologic testing. Here, we searched for cases of dual antigen MN at Mayo Clinic and Arkana Laboratories with the diagnosis established by light/electron microscopy and IF.</div></div><div><h3>Methods</h3><div>At Mayo Clinic, we performed laser capture microdissection of glomeruli followed by liquid chromatography tandem mass spectrometry (LC MS/MS) on paraffin-embedded kidney biopsy tissue to detect 12 MN antigens.</div></div><div><h3>Results</h3><div>Nine cases of dual antigen MN (four at Mayo Clinic, five at Arkana Laboratories) were confirmed by both LC MS/MS and IHC/IF. The detected antigens were NELL1 + CNTN1 (two cases), NCAM1 + EXT1/2 (two cases), and one case each NDNF + NELL1, NELL1 + PLA2R1, THSD7A + PLA2R1, PCDH7 + PLA2R1, and CNTN1 + PCDH7. Median age at diagnosis was 68 years (range 23-84). Eight patients presented with nephrotic syndrome and microscopic hematuria. Median serum creatinine at diagnosis was 1 mg/dL. The underlying conditions, when present, and serological characteristics, correlated with the involved antigens. The frequency at Mayo Clinic was 2.6% of PLA2R1-negative MN cases.</div></div><div><h3>Conclusions</h3><div>Given that IHC/IF and LC MS/MS for MN antigen detection are typically not pursued in PLA2R1-associated MN, dual-antigen MN is likely underdiagnosed. Dual-antigen MN can involve a variety of MN antigens, including those that are podocyte-expressed, transmembrane, or secreted. Most patients with MN present with nephrotic syndrome and microscopic hematuria. Further studies are needed to understand the pathophysiology of dual-antigen MN and determine their role both in the therapeutic approach and clinical outcomes. Our findings suggest that LC MS/MS is a valuable methodology for detection of dual antigen MN.</div></div>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages 217-224"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145434938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.kint.2025.09.031
Caroline Duineveld , Jack F.M. Wetzels
The development of anticomplement therapies provides an impetus to classify patients with C3 glomerulopathy/immune complex membranoproliferative glomerulonephritis in homogeneous subgroups, which reflect disease etiology. A recent hierarchical cluster analysis identified 5 clusters. A web-based tool allows clinicians to classify their patients. Although the study paves the way for future research, clinicians should be aware of the many limitations and await validation studies before using the tool.
{"title":"Disentangling disease heterogeneity in C3 glomerulopathies: a slippery road","authors":"Caroline Duineveld , Jack F.M. Wetzels","doi":"10.1016/j.kint.2025.09.031","DOIUrl":"10.1016/j.kint.2025.09.031","url":null,"abstract":"<div><div>The development of anticomplement therapies provides an impetus to classify patients with C3 glomerulopathy/immune complex membranoproliferative glomerulonephritis in homogeneous subgroups, which reflect disease etiology. A recent hierarchical cluster analysis identified 5 clusters. A web-based tool allows clinicians to classify their patients. Although the study paves the way for future research, clinicians should be aware of the many limitations and await validation studies before using the tool.</div></div>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages 40-43"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145880397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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