Pub Date : 2026-01-01DOI: 10.1016/j.kint.2025.10.003
Franz Schaefer
This editorial comments on the report on a 2023 multistakeholder workshop addressing the development of sodium-glucose cotransporter-2 inhibitors for children with chronic kidney disease. Despite adult trials showing strong renal and cardiovascular benefits, pediatric studies are lacking because regulatory waivers excluded this population. Workshop participants emphasized urgent medical need, but also highlighted challenges: pediatric chronic kidney disease differs from adults, with congenital anomalies and nonglomerular disorders predominating, slower progression, and less proteinuria, limiting extrapolation from adult data. Safety concerns specific to children include dehydration, infections, and growth, bone, and neurodevelopmental effects. Lessons from adult trials underscore the need for pediatric-specific end points and biomarkers, including for cardiovascular outcomes. Recent regulatory actions, including the US Food and Drug Administration’s mandate for pediatric empagliflozin studies, mark progress. Upcoming clinical trials (A Study to Find Out How EMPAgliflozin is Tolerated and if it Helps Children and Adolescents With Chronic KIDNEY Disease [EMPA-KIDNEY-Kids], Phase 3 Clinical Trial with Dapagliflozin in Chronic Kidney Disease in Adolescents and Young Adult Patients [DOUBLE-PROTECT] Alport) will require collaborative international efforts by the pediatric nephrology community to close the knowledge gap and ensure equitable access to renoprotective therapies for children with chronic kidney disease.
{"title":"SGLT-2 inhibition in pediatric CKD: advances, challenges, and opportunities","authors":"Franz Schaefer","doi":"10.1016/j.kint.2025.10.003","DOIUrl":"10.1016/j.kint.2025.10.003","url":null,"abstract":"<div><div>This editorial comments on the report on a 2023 multistakeholder workshop addressing the development of sodium-glucose cotransporter-2 inhibitors for children with chronic kidney disease. Despite adult trials showing strong renal and cardiovascular benefits, pediatric studies are lacking because regulatory waivers excluded this population. Workshop participants emphasized urgent medical need, but also highlighted challenges: pediatric chronic kidney disease differs from adults, with congenital anomalies and nonglomerular disorders predominating, slower progression, and less proteinuria, limiting extrapolation from adult data. Safety concerns specific to children include dehydration, infections, and growth, bone, and neurodevelopmental effects. Lessons from adult trials underscore the need for pediatric-specific end points and biomarkers, including for cardiovascular outcomes. Recent regulatory actions, including the US Food and Drug Administration’s mandate for pediatric empagliflozin studies, mark progress. Upcoming clinical trials (A Study to Find Out How EMPAgliflozin is Tolerated and if it Helps Children and Adolescents With Chronic KIDNEY Disease [EMPA-KIDNEY-Kids], Phase 3 Clinical Trial with Dapagliflozin in Chronic Kidney Disease in Adolescents and Young Adult Patients [DOUBLE-PROTECT] Alport) will require collaborative international efforts by the pediatric nephrology community to close the knowledge gap and ensure equitable access to renoprotective therapies for children with chronic kidney disease.</div></div>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages 2-5"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145883606","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.2025.07.014
Anita T. Layton
{"title":"Sexual dimorphism of age and nephron segment specific gene expression in mouse kidneys: insights from multi-omic and spatial analysis","authors":"Anita T. Layton","doi":"10.1016/j.kint.2025.07.014","DOIUrl":"10.1016/j.kint.2025.07.014","url":null,"abstract":"","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages 25-27"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018005","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.2025.08.035
Ariela Benigni , Erica Daina , Henry Löffler-Wirth , Rossella Piras , Miriam Rigoldi , Maria Schmidt , Camillo Carrara , Roberta Donadelli , Zahra Imanifard , Caterina Mele , Marta Alberti , Maddalena Marasà , Carolina Martinatto , Elena Bresin , Sara Gamba , Lisa Quadri , Giliane Nanchen , Marina Vivarelli , Francesco Emma , Gaetano La Manna , Zanella Monica
Introduction
Membranoproliferative glomerulonephritis (MPGN) is currently stratified into complement C3 glomerulopathy (C3G) and immune complex-mediated MPGN (IC-MPGN). However, classification is subject to continued debate.
Methods
Here, we applied hierarchical clustering to a much larger cohort of patients with C3G/IC-MPGN (295 individuals), extensively characterized for genetic and autoimmune complement abnormalities, with the goal of unraveling specific disease patterns. We also designed a user-friendly web application that with input of data at diagnosis could make cluster classification clinically applicable.
Results
Five clusters with unique phenotypic and complement profiles were identified. Cluster 1 and 2 patients showed systemic complement activation until C5. Consistently, C5 nephritic factor and anti-factor B antibodies were prevalent in these clusters. Cluster 2 was distinguished from cluster 1 for classical pathway activation markers in biopsy. Cluster 3 showed C3-restricted systemic complement activation associated with the prevalence of C3 nephritic factor. Cluster 4 and 5 patients shared a normal complement profile and intense glomerular C3 staining, consistent with solid-phase complement activation, but cluster 5 distinguished for the higher prevalence of genetic abnormalities. Cluster 4 patients had the highest incidence of kidney failure during follow-up, while cluster 1 had the best kidney prognosis. However, clusters 1 and 2 showed a high risk of post-transplant recurrence. Through our web application, we could visually compare the predicted profile of new patients with those of patients included in clustering analysis and assign these patients to different clusters. The cluster-based classification allows etiologic diagnosis of C3G/IC-MPGN and had better prognostic value than current approaches.
Conclusions
Our proposed strategy may possibly guide anti-complement treatment.
{"title":"Hierarchical clustering uncovered disease patterns and further untangled complexities in immune complex-mediated idiopathic MPGN and C3 glomerulopathy","authors":"Ariela Benigni , Erica Daina , Henry Löffler-Wirth , Rossella Piras , Miriam Rigoldi , Maria Schmidt , Camillo Carrara , Roberta Donadelli , Zahra Imanifard , Caterina Mele , Marta Alberti , Maddalena Marasà , Carolina Martinatto , Elena Bresin , Sara Gamba , Lisa Quadri , Giliane Nanchen , Marina Vivarelli , Francesco Emma , Gaetano La Manna , Zanella Monica","doi":"10.1016/j.kint.2025.08.035","DOIUrl":"10.1016/j.kint.2025.08.035","url":null,"abstract":"<div><h3>Introduction</h3><div>Membranoproliferative glomerulonephritis (MPGN) is currently stratified into complement C3 glomerulopathy (C3G) and immune complex-mediated MPGN (IC-MPGN). However, classification is subject to continued debate.</div></div><div><h3>Methods</h3><div>Here, we applied hierarchical clustering to a much larger cohort of patients with C3G/IC-MPGN (295 individuals), extensively characterized for genetic and autoimmune complement abnormalities, with the goal of unraveling specific disease patterns. We also designed a user-friendly web application that with input of data at diagnosis could make cluster classification clinically applicable.</div></div><div><h3>Results</h3><div>Five clusters with unique phenotypic and complement profiles were identified. Cluster 1 and 2 patients showed systemic complement activation until C5. Consistently, C5 nephritic factor and anti-factor B antibodies were prevalent in these clusters. Cluster 2 was distinguished from cluster 1 for classical pathway activation markers in biopsy. Cluster 3 showed C3-restricted systemic complement activation associated with the prevalence of C3 nephritic factor. Cluster 4 and 5 patients shared a normal complement profile and intense glomerular C3 staining, consistent with solid-phase complement activation, but cluster 5 distinguished for the higher prevalence of genetic abnormalities. Cluster 4 patients had the highest incidence of kidney failure during follow-up, while cluster 1 had the best kidney prognosis. However, clusters 1 and 2 showed a high risk of post-transplant recurrence. Through our web application, we could visually compare the predicted profile of new patients with those of patients included in clustering analysis and assign these patients to different clusters. The cluster-based classification allows etiologic diagnosis of C3G/IC-MPGN and had better prognostic value than current approaches.</div></div><div><h3>Conclusions</h3><div>Our proposed strategy may possibly guide anti-complement treatment.</div></div>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages 178-195"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261645","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.2025.09.023
Xuezhu Li , John Cijiang He , Kyung Lee
Individuals with metabolic syndrome are at an increased risk of developing chronic kidney disease or accelerating the progression of preexisting chronic kidney disease. Furthermore, such individuals are predisposed to developing diabetes, increasing their susceptibility to diabetic kidney disease (DKD). Current DKD treatments have expanded to include renin-angiotensin-aldosterone system inhibitors, sodium-glucose cotransporter-2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists, which confer significant renoprotection. Nevertheless, DKD continues to persist and progress, underscoring the need for the development of novel therapeutic strategies that additionally target the underlying pathophysiological mechanisms in DKD. This mini review highlights several emerging targets from preclinical models of DKD and metabolic-associated kidney disease and provides a brief overview of the pathways involved in their mechanisms of renoprotection.
{"title":"New potential therapeutic targets of metabolic disorder–associated kidney disease and diabetic kidney disease","authors":"Xuezhu Li , John Cijiang He , Kyung Lee","doi":"10.1016/j.kint.2025.09.023","DOIUrl":"10.1016/j.kint.2025.09.023","url":null,"abstract":"<div><div>Individuals with metabolic syndrome are at an increased risk of developing chronic kidney disease or accelerating the progression of preexisting chronic kidney disease. Furthermore, such individuals are predisposed to developing diabetes, increasing their susceptibility to diabetic kidney disease (DKD). Current DKD treatments have expanded to include renin-angiotensin-aldosterone system inhibitors, sodium-glucose cotransporter-2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists, which confer significant renoprotection. Nevertheless, DKD continues to persist and progress, underscoring the need for the development of novel therapeutic strategies that additionally target the underlying pathophysiological mechanisms in DKD. This mini review highlights several emerging targets from preclinical models of DKD and metabolic-associated kidney disease and provides a brief overview of the pathways involved in their mechanisms of renoprotection.</div></div>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages 81-88"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145369469","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.2025.10.002
Lovis Kling , Ralph Kettritz
Antineutrophil cytoplasmic autoantibody–associated vasculitides can be classified by clinical phenotype or antineutrophil cytoplasmic autoantibody specificity, with overlapping yet distinct characteristics. Transcriptomic analyses of kidney biopsies from 2 French antineutrophil cytoplasmic autoantibody–associated vasculitis (AAV) cohorts revealed a pronounced type I interferon signature in microscopic polyangiitis (microscopic polyangiitis/myeloperoxidase-AAV) compared with granulomatosis with polyangiitis (granulomatosis with polyangiitis/proteinase 3-AAV). Among biopsies with high interferon scores, 66% were myeloperoxidase-AAV and 28% proteinase 3-AAV. The interferon score was associated with decreased kidney survival. These findings highlight AAV patient heterogeneity and support targeted treatment approaches.
{"title":"Similar and yet not quite the same: unmasking distinct type I interferon signatures in ANCA vasculitis","authors":"Lovis Kling , Ralph Kettritz","doi":"10.1016/j.kint.2025.10.002","DOIUrl":"10.1016/j.kint.2025.10.002","url":null,"abstract":"<div><div>Antineutrophil cytoplasmic autoantibody–associated vasculitides can be classified by clinical phenotype or antineutrophil cytoplasmic autoantibody specificity, with overlapping yet distinct characteristics. Transcriptomic analyses of kidney biopsies from 2 French antineutrophil cytoplasmic autoantibody–associated vasculitis (AAV) cohorts revealed a pronounced type I interferon signature in microscopic polyangiitis (microscopic polyangiitis/myeloperoxidase-AAV) compared with granulomatosis with polyangiitis (granulomatosis with polyangiitis/proteinase 3-AAV). Among biopsies with high interferon scores, 66% were myeloperoxidase-AAV and 28% proteinase 3-AAV. The interferon score was associated with decreased kidney survival. These findings highlight AAV patient heterogeneity and support targeted treatment approaches.</div></div>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages 34-37"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145883600","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.2025.09.009
William E. Smoyer , Barbara S. Gillespie , Louise Oni , Carla Nester , Robert G. Nelson , Petter Bjornstad , Hiddo J.L. Heerspink , Michelle Denburg , Oliver Gross , Jan Marquard , Dominik Steubl , Mark D. Lim , Cesia Creighton , Seyi Balogun , Lauren Eva , Kelly Helm , Joshua M. Tarnoff , Shamir Tuchman , Mona Khurana , Lily Mulugeta , Howard Trachtman
Pediatric patients with chronic kidney disease (CKD) are treated with nonspecific therapies such as renin-angiotensin-aldosterone system inhibitors; however, there are no approved therapies to slow the progression of pediatric CKD across its diverse etiologies. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have demonstrated efficacy in slowing the rate of decline in estimated glomerular filtration rate and CKD progression in adults. These therapies hold the promise of similar clinical benefit for pediatric patients with CKD by potentially delaying progression to kidney failure. However, clinical data informing the efficacy, safety, and dosing of these products in pediatric patients with CKD are lacking. To address this issue, a 1.5-day workshop was convened by the Kidney Health Initiative and NephCure, with participation from stakeholders that included regulators, National Institutes of Health representatives, trialists, clinicians and investigators, industry representatives, patient advocates, and caregivers. The goal of the workshop was to elucidate the challenges and strategize approaches to evaluate the use of SGLT2is in pediatric patients with CKD. To this end, presentations and discussions at the workshop focused on the data supporting the degree to which the course of CKD and expected treatment responses between adult and pediatric populations with CKD are similar, and hence, the degree to which, if any, data from the trials of SGLT2is in adults could be extrapolated to pediatric patients with CKD. Discussions also focused on trial design feasibility, end points, gaps in knowledge, and safety considerations for SGLT2is in pediatric CKD. The workshop proposed pathways to advance the evaluation of SGLT2is as therapeutic agents to treat glomerular and nonglomerular pediatric CKD while identifying remaining challenges and research priorities.
{"title":"Strategies for the development of sodium-glucose cotransporter-2 inhibitors for kidney protection in pediatric chronic kidney disease: proceedings of a workshop meeting in July 2023","authors":"William E. Smoyer , Barbara S. Gillespie , Louise Oni , Carla Nester , Robert G. Nelson , Petter Bjornstad , Hiddo J.L. Heerspink , Michelle Denburg , Oliver Gross , Jan Marquard , Dominik Steubl , Mark D. Lim , Cesia Creighton , Seyi Balogun , Lauren Eva , Kelly Helm , Joshua M. Tarnoff , Shamir Tuchman , Mona Khurana , Lily Mulugeta , Howard Trachtman","doi":"10.1016/j.kint.2025.09.009","DOIUrl":"10.1016/j.kint.2025.09.009","url":null,"abstract":"<div><div>Pediatric patients with chronic kidney disease (CKD) are treated with nonspecific therapies such as renin-angiotensin-aldosterone system inhibitors; however, there are no approved therapies to slow the progression of pediatric CKD across its diverse etiologies. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have demonstrated efficacy in slowing the rate of decline in estimated glomerular filtration rate and CKD progression in adults. These therapies hold the promise of similar clinical benefit for pediatric patients with CKD by potentially delaying progression to kidney failure. However, clinical data informing the efficacy, safety, and dosing of these products in pediatric patients with CKD are lacking. To address this issue, a 1.5-day workshop was convened by the Kidney Health Initiative and NephCure, with participation from stakeholders that included regulators, National Institutes of Health representatives, trialists, clinicians and investigators, industry representatives, patient advocates, and caregivers. The goal of the workshop was to elucidate the challenges and strategize approaches to evaluate the use of SGLT2is in pediatric patients with CKD. To this end, presentations and discussions at the workshop focused on the data supporting the degree to which the course of CKD and expected treatment responses between adult and pediatric populations with CKD are similar, and hence, the degree to which, if any, data from the trials of SGLT2is in adults could be extrapolated to pediatric patients with CKD. Discussions also focused on trial design feasibility, end points, gaps in knowledge, and safety considerations for SGLT2is in pediatric CKD. The workshop proposed pathways to advance the evaluation of SGLT2is as therapeutic agents to treat glomerular and nonglomerular pediatric CKD while identifying remaining challenges and research priorities.</div></div>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages 57-63"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153426","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.2025.09.028
Burcin Altun , Gexin Zhao , Baomei Wang , Xuming Mao , Silvio Manfredo-Vieira , Elinor Willis , Enrico Radaelli , Emma E. Goodman , Alina C. Boesteanu , Saar I. Gill , Darshil R. Patel , Steven Wong , Ebony Cottman-Thomas , Jonathan J. Hogan , Aimee S. Payne
Introduction
Phospholipase A2 receptor (PLA2R)–associated membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults, driven by autoantibodies that target PLA2R on kidney podocytes. Antibody-based therapy with rituximab induces broad B-cell depletion but is associated with risks of serious infection and reduced efficacy in patients with high proteinuria. Here, we determined the feasibility of developing chimeric autoantibody receptor T-cell (CAART) therapy for PLA2R-specific B-cell depletion in PLA2R MN.
Methods
PLA2R-CAART was produced by T-cell lentiviral transduction. In vitro cytotoxicity and specificity were evaluated against B-cell lines targeting PLA2R immunodominant epitopes and primary PLA2R MN B cells. Adsorption of PLA2R MN IgG was evaluated to determine the extent of pathogenic autoantibody targeting by candidate PLA2R-CAART designs. Specific cytotoxicity, engraftment capability, and off-target toxicity were evaluated in a xenografted anti-PLA2R Nalm-6 preclinical mouse model, with additional toxicology screening by human membrane proteome arrays.
Results
We engineered CAARTs targeting key PLA2R epitopes to selectively deplete autoreactive B cells. C17- and C178-CAART (encompassing CysR, CTLD1, and CTLD7, with/without CTLD8 domains) were successfully expressed on primary T cells and demonstrated specific in vitro cytotoxicity against anti-PLA2R B-cell lines targeting CysR, CTLD1, and CTLD7 epitopes. In co-incubation assays with primary B cells or plasma from patients with MN, C17- and C178-CAART significantly reduced anti-PLA2R B cells and adsorbed 69-97% of plasma anti-PLA2R antibody reactivity. In vivo, C17- and C178-CAART treatment in the Nalm-6 xenograft model resulted in significant reduction in target cell outgrowth with C17-CAART showing slight but consistently increased cytotoxic activity. Specificity testing through comprehensive in vivo pathologic analysis and a high-throughput membrane proteome array analysis showed no significant off-target binding for either C17- or C178-CAART.
Conclusions
Our findings establish preclinical proof-of-concept for the therapeutic potential of antigen-specific B-cell depletion by PLA2R-CAART. Additional studies are required to determine clinical feasibility of PLA2R-CAART for PLA2R MN therapy.
{"title":"Preclinical evaluation of antigen-specific B-cell depletion for phospholipase A2 receptor membranous nephropathy with chimeric autoantibody receptor T cells","authors":"Burcin Altun , Gexin Zhao , Baomei Wang , Xuming Mao , Silvio Manfredo-Vieira , Elinor Willis , Enrico Radaelli , Emma E. Goodman , Alina C. Boesteanu , Saar I. Gill , Darshil R. Patel , Steven Wong , Ebony Cottman-Thomas , Jonathan J. Hogan , Aimee S. Payne","doi":"10.1016/j.kint.2025.09.028","DOIUrl":"10.1016/j.kint.2025.09.028","url":null,"abstract":"<div><h3>Introduction</h3><div>Phospholipase A2 receptor (PLA2R)–associated membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults, driven by autoantibodies that target PLA2R on kidney podocytes. Antibody-based therapy with rituximab induces broad B-cell depletion but is associated with risks of serious infection and reduced efficacy in patients with high proteinuria. Here, we determined the feasibility of developing chimeric autoantibody receptor T-cell (CAART) therapy for PLA2R-specific B-cell depletion in PLA2R MN.</div></div><div><h3>Methods</h3><div>PLA2R-CAART was produced by T-cell lentiviral transduction. <em>In vitro</em> cytotoxicity and specificity were evaluated against B-cell lines targeting PLA2R immunodominant epitopes and primary PLA2R MN B cells. Adsorption of PLA2R MN IgG was evaluated to determine the extent of pathogenic autoantibody targeting by candidate PLA2R-CAART designs. Specific cytotoxicity, engraftment capability, and off-target toxicity were evaluated in a xenografted anti-PLA2R Nalm-6 preclinical mouse model, with additional toxicology screening by human membrane proteome arrays.</div></div><div><h3>Results</h3><div>We engineered CAARTs targeting key PLA2R epitopes to selectively deplete autoreactive B cells. C17- and C178-CAART (encompassing CysR, CTLD1, and CTLD7, with/without CTLD8 domains) were successfully expressed on primary T cells and demonstrated specific <em>in vitro</em> cytotoxicity against anti-PLA2R B-cell lines targeting CysR, CTLD1, and CTLD7 epitopes. In co-incubation assays with primary B cells or plasma from patients with MN, C17- and C178-CAART significantly reduced anti-PLA2R B cells and adsorbed 69-97% of plasma anti-PLA2R antibody reactivity. <em>In vivo</em>, C17- and C178-CAART treatment in the Nalm-6 xenograft model resulted in significant reduction in target cell outgrowth with C17-CAART showing slight but consistently increased cytotoxic activity. Specificity testing through comprehensive <em>in vivo</em> pathologic analysis and a high-throughput membrane proteome array analysis showed no significant off-target binding for either C17- or C178-CAART.</div></div><div><h3>Conclusions</h3><div>Our findings establish preclinical proof-of-concept for the therapeutic potential of antigen-specific B-cell depletion by PLA2R-CAART. Additional studies are required to determine clinical feasibility of PLA2R-CAART for PLA2R MN therapy.</div></div>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages 89-100"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145412020","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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