Journal of The American Society of Nephrology最新文献

{"title":"Macrophage IgG Recycling Couples Glomerular IgG Accumulation to Podocyte Senescence in Obesity-Related Glomerulopathy.","authors":"Zikang Liu, Binbin Dai, Yuxuan Jin, Jiwen Bao, Hanxue Zhao, Yurong Lin, Hongtu Hu, Yangbin Pan","doi":"10.1681/ASN.0000001243","DOIUrl":"https://doi.org/10.1681/ASN.0000001243","url":null,"abstract":"<p><strong>Background: </strong>Obesity-related glomerulopathy is increasingly common, yet its pathogenesis remains poorly understood. This study aimed to elucidate the mechanisms by which nonspecific glomerular IgG deposition promotes podocyte senescence in obesity-related glomerulopathy, thereby expanding potential therapeutic options.</p><p><strong>Methods: </strong>Kidney samples from patients with obesity-related glomerulopathy and diet-induced obese mice were used to compare glomerular IgG localization and abundance in obese versus control states. Causality between glomerular IgG accumulation and podocyte senescence was assessed by exogenous IgG supplementation and B cell deficiency mice. Primary podocytes were IgG-stimulated for transcriptomic and lipidomic profiling, and sphingomyelin phosphodiesterase 3 (Smpd3) was validated by in vitro and in vivo loss-of-function studies. Macrophage-specific FcRn deletion and anti-CD20 therapy were further used to evaluate IgG-targeted strategies for mitigating podocyte senescence and injury in ORG.</p><p><strong>Results: </strong>Glomerular IgG deposition was markedly increased in both patients with obesity-related glomerulopathy and mice with diet-induced obesity. Exogenous IgG supplementation in non-obese mice reproduced the glomerular IgG accumulation and podocyte senescence observed in HFD fed mice. Conversely, B-cell null diet-induced obese mice and anti-CD20 treated diet-induced obese mice showed greatly reduced glomerular IgG levels and attenuated podocyte injury. Mechanistically, IgG exposure activated podocyte sphingolipid metabolism, notably upregulating Smpd3 and increasing intra-podocyte ceramide. In vitro and in vivo Smpd3 knockdown prevented IgG induced ceramide accumulation and podocyte senescence. Obesity also heightened glomerular macrophage infiltration, and macrophage depletion or macrophage-specific FcRn knockout significantly reduced glomerular IgG deposition and protected against podocyte injury and senescence.</p><p><strong>Conclusions: </strong>FcRn-expressing macrophages increased obesity-induced IgG retention in glomeruli, which led to podocyte ceramide overload and senescence.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891893","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}

{"title":"Risk, Not Just Rate: Toward Individualized Correction in Hyponatremia.","authors":"Harish Seethapathy, Sahir Kalim, Sagar U Nigwekar","doi":"10.1681/ASN.0000001270","DOIUrl":"https://doi.org/10.1681/ASN.0000001270","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887928","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}

{"title":"Chimeric HLA Antibody Receptor (CHAR) T Cells to Specifically Eliminate HLA-DQ-Specific B Cells.","authors":"Carolt Arana, Ilse Gille, Renate Hagedoorn, Ainhoa García-Busquets, Hannah C M Schenk, Sergi Betriu, Dennis F G Remst, Ellen M W van der Meer-Prins, Yvonne J H de Vaal, Kim H Voogt-Bakker, Rico Buchli, Aiko P J de Vries, Manel Juan, Cynthia S M Kramer, Eduard Palou, Dave L Roelen, Fritz Diekmann, Mirjam H M Heemskerk, Jordi Rovira, Sebastiaan Heidt","doi":"10.1681/ASN.0000001244","DOIUrl":"https://doi.org/10.1681/ASN.0000001244","url":null,"abstract":"<p><strong>Background: </strong>CAR T cell therapy has revolutionized the treatment of hematological malignancies by effectively eliminating tumor cells. In the field of kidney transplantation, comparable cellular therapies are being explored to facilitate transplantation and prevent graft rejection. Chimeric HLA antibody receptor (CHAR) T cells are a promising therapy for eliminating HLA-specific B cells in sensitized patients and potentially ameliorating antibody-mediated rejection. We previously demonstrated that HLA class I CHAR T cells selectively eliminated HLA class I-specific B cells with high specificity. Since HLA sensitization is most often directed against HLA-DQ of the allograft, we developed HLA-DQ2 and HLA-DQ7 CHAR T cells to target B cells with corresponding HLA specificity.</p><p><strong>Methods: </strong>We designed viral vectors encoding HLA-DQ CHARs composed of HLA-DQA1*05:01 alpha chain with either HLA-DQB1*02:01 (HLA-DQ2) or HLA-DQB1*03:01 (HLA-DQ7) beta chains, CLIP peptide, and intracellular 4-1BB costimulatory and CD3ζ signaling domains. Upon production of HLA-DQ CHAR T cells, we evaluated CHAR expression, cytotoxic activity, production of cytokines and cytotoxic mediators, and sensitivity to immunosuppressive drugs in in vitro models. We further assessed the cytotoxic activity of HLA-DQ CHAR T cells in an immunodeficient mouse model and in primary material from sensitized individuals.</p><p><strong>Results: </strong>CHAR-transduced Jurkat Triple Parameter Reporter (JurkatTPR) cells expressing reporter constructs for T cell activation markers showed robust activation upon specific stimulation. Primary CD8+ T cells expressing HLA-DQ2 and HLA-DQ7 CHAR molecules specifically eliminated HLA-DQ2- or HLA-DQ7-specific B cells, respectively, and produced interferon gamma, soluble Fas ligand, perforin, and granzyme B. Maintenance immunosuppressive drug regimens initiated at the time of co-incubation with target cells had limited effects on CHAR T-cell functionality. Finally, HLA-DQ CHAR T cells effectively eliminated HLA-DQ-specific B cells in an in vivo mouse model, as well as in primary material from sensitized individuals.</p><p><strong>Conclusions: </strong>HLA-DQ2 and HLA-DQ7 CHAR T cells, the first HLA class II CHAR T cells, selectively and effectively eliminated corresponding HLA-DQ-specific B cells in vitro, in vivo, and in primary material from sensitized individuals.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887899","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}

{"title":"ASN Kidney Health Guidance on the Cardiovascular-Kidney-Metabolic Syndrome.","authors":"Nisha Bansal, Petter Bjornstad, Adam P Bress, Tara I Chang, Xingxing Cheng, Michelle M Estrella, Alan S Go, Amy K Mottl, Sankar D Navaneethan, Brendon L Neuen, Brian S Rifkin, Kim Zuber, Alexander R Chang","doi":"10.1681/ASN.0000001231","DOIUrl":"10.1681/ASN.0000001231","url":null,"abstract":"<p><strong>Key points: </strong>The cardiovascular-kidney-metabolic (CKM) syndrome framework has important implications in the care of people with kidney diseases. Cardiovascular screening is important in people with kidney diseases, but the approach may differ in this high-risk population. Multiple pharmacotherapies for CKM syndrome offer significant cardiovascular and kidney benefits.</p><p><p>Cardiovascular-kidney-metabolic (CKM) syndrome highlights the interconnected nature of cardiovascular disease, CKD, and metabolic dysfunction and underscores the need for integrated approaches to prevention and treatment. Patients with kidney diseases are at markedly elevated risk for atherosclerotic cardiovascular events, heart failure, kidney failure, and premature mortality across the spectrum of kidney disease severity. Recent advances in therapeutics, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1)-based therapies, and nonsteroidal mineralocorticoid receptor antagonists, alongside established renin-angiotensin system inhibitors and lipid-lowering therapies, have transformed the management of CKM by demonstrating both cardiovascular and kidney benefits. However, important gaps remain in applying the CKM framework to patients with kidney diseases, particularly among individuals with advanced CKD, kidney failure treated with dialysis, kidney transplant recipients, younger and older individuals, and those with nonmetabolic kidney diseases including glomerular disorders. This American Society of Nephrology Kidney Health Guidance provides practical guidance for nephrology clinicians on screening, risk stratification, and pharmacologic management across the CKM spectrum. The guidance emphasizes the importance of longitudinal assessment of estimated glomerular filtration rate and albuminuria as foundational markers of cardiovascular and kidney risk, including the role of cardiac biomarkers and imaging. Integration of cardiovascular and kidney risk prediction models, including the American Heart Association Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) equations and the Kidney Failure Risk Equation (KFRE), may support early identification of high-risk patients and guide treatment intensification. The guidance also reviews evidence supporting sequential and combination approaches to CKM therapies, strategies for managing adverse effects, and special considerations for CKD subpopulations where data are more limited. Adoption of a CKM framework in nephrology practice promotes coordinated, multidisciplinary care and provides an opportunity to shift from organ-specific management toward a more holistic approach aimed at reducing cardiovascular events, slowing kidney disease progression, and improving patient-centered outcomes across the continuum of kidney disease.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881050","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}

{"title":"Executive Summary of the ASN Kidney Health Guidance on the Cardiovascular‑Kidney‑Metabolic Syndrome.","authors":"Sankar D Navaneethan, Brian Rifkin, Amy K Mottl","doi":"10.1681/ASN.0000001230","DOIUrl":"https://doi.org/10.1681/ASN.0000001230","url":null,"abstract":"<p><strong>Key points: </strong>The cardiovascular‑kidney‑metabolic framework encourages routine assessment of cardiovascular risk, metabolic health, and kidney function. Cardiovascular risk equations should be used in patients with CKD to direct preventive therapies and promote coordination of care to optimize outcomes. Comprehensive therapy building upon foundational CKD management is essential to minimize treatment gaps and improve cardiovascular‑kidney‑metabolic outcomes.</p><p><p>The recent release of the inaugural AHA/ACC/ADA/ASN Guideline for the Prevention, Detection, Evaluation, and Management of Cardiovascular-Kidney-Metabolic (CKM) Syndrome calls for health care professionals across disciplines to broaden their practice to include the full spectrum of these interconnected disease states. This ASN Kidney Health Guidance aims to unite the nephrology community in this effort, highlighting the central role kidney disease plays in CKM syndrome and providing CKD-specific considerations. CKD is often complicated by comorbid cardiovascular and metabolic diseases, and regular evaluation of patients should include screening and management across disease states. The Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) equation should be integrated along with kidney outcome predictors for routine patient counseling and risk assessment. Lifestyle modifications, including regular physical activity, avoidance of tobacco products, and adoption of a healthy diet and sleep patterns, underpin CKM management. Both renin-angiotensin system inhibitors and sodium-glucose cotransporter 2 inhibitors are foundational therapies in CKD for the prevention of cardiovascular and kidney end points, and glucagon-like peptide-1-based therapies and nonsteroidal mineralocorticoid receptor antagonists may be added according to an individual patient's cardiovascular and metabolic risk profile. CKM therapies may be initiated simultaneously or in rapid sequence according to shared decision making, but therapeutic inertia must be avoided. Cardiovascular disease mitigation should also include lipid management for primary and secondary prevention. Evidence supporting the benefits of CKM treatments in people with glomerulonephritis, those with kidney transplant, those on dialysis with kidney failure treated with maintenance dialysis, pediatric populations, older adults, and those with frailty is limited. However, screening and diagnosis of CKM syndrome are critical, and these cardiokidney protective therapies may be used with shared decision making. Diabetes and obesity are extremely common in people living with kidney disease; both are major contributors to CKD progression. CKD poses a major risk of cardiovascular morbidity and mortality. Hence, nephrology team members should play a vital role in the diagnosis, treatment, and implementation of a holistic and multidisciplinary approach for the well-being of patients with kidney diseases.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881059","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}

{"title":"Impaired BCAA Catabolism Drives Peritoneal Fibrosis via BCKA-Mediated Suppression of the Pentose Phosphate Pathway.","authors":"Jiayang Li, Tiangang Wu, Junhao Dai, Xin Zhao, Svetlana Reilly, Xin Liu, Dongliang Zhang, Hong Xin, Nan Zhu, Zhiping Li, Zanzhe Yu, Xuemei Zhang","doi":"10.1681/ASN.0000001241","DOIUrl":"https://doi.org/10.1681/ASN.0000001241","url":null,"abstract":"<p><strong>Background: </strong>Peritoneal dialysis (PD) is a life-sustaining therapy for kidney failure, yet its long-term viability is compromised by progressive peritoneal fibrosis in some patients. Currently, reliable treatment options are lacking as the pathogenesis remains poorly understood, with the metabolic underpinnings of fibrotic progression remaining particularly elusive.</p><p><strong>Methods: </strong>Using a physiologically relevant framework comprising human primary mesothelial cells and a PD fluid-exposed mouse model, we performed bidirectional genetic and pharmacological modulation of branched-chain amino acid catabolism. Integrated proteomic and metabolomic analyses were conducted to investigate downstream metabolic consequences.</p><p><strong>Results: </strong>We identified profound impairment in branched-chain amino acid (BCAA) catabolism, centered on a functional bottleneck at the rate-limiting branched-chain α-ketoacid dehydrogenase complex, as a metabolic hallmark of peritoneal fibrosis. Functional uncoupling of the amino acids from their ketoacid derivatives indicated that branched-chain α-ketoacid (BCKA) burden was more closely linked to the fibrotic phenotype than BCAA abundance alone. Mechanistically, BCKA burden was associated with reduced glucose-6-phosphate dehydrogenase expression and activity, lower NADPH-generating capacity, and increased intracellular oxidant burden.</p><p><strong>Conclusions: </strong>Together, these findings showed that BCKA burden, rather than BCAA abundance alone, more closely tracked fibrotic responses and was linked to reduced pentose phosphate pathway-associated redox capacity in peritoneal fibrosis.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874409","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}

{"title":"Recurrent Antibiotic-Treated Pyelonephritis Depletes Renal Functional Reserve Despite Preserved Basal GFR in a Reflux-Prone Mouse Model.","authors":"Evan A Rajadhyaksha, Samuel Arregui, Vijay Saxena, Alleé Shaw, Jennifer L Anderson, Sayeh Gholampoor, Gokul Achayaraj, Rose Odom, Danielle E Soranno, David S Hains, Andrew L Schwaderer","doi":"10.1681/ASN.0000001166","DOIUrl":"10.1681/ASN.0000001166","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":"2027-2029"},"PeriodicalIF":9.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148176135","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}

{"title":"Clarifying Crossover Interpretation and Volume-Signal Assessment in ASSIST.","authors":"Dongmei Cheng, Lin Zhan, Huan Zhou","doi":"10.1681/ASN.0000001141","DOIUrl":"10.1681/ASN.0000001141","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":"2079-2080"},"PeriodicalIF":9.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148205224","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}

{"title":"Correction to: HSP72 Inhibits Smad3 Activation and Nuclear Translocation in Renal Epithelial-to-Mesenchymal Transition.","authors":"Yi Zhou, Haiping Mao, Shu Li, Shirong Cao, Zhijian Li, Shougang Zhuang, Jinjin Fan, Xiuqing Dong, Steven C Borkan, Yihan Wang, Xueqing Yu","doi":"10.1681/ASN.0000001114","DOIUrl":"10.1681/ASN.0000001114","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":"2082-2084"},"PeriodicalIF":9.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147616277","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}

{"title":"Alport: Renaming an Extended Clinical Spectrum.","authors":"Rachel Lennon, Jeffrey H Miner, Judy Savige, B André Weinstock, Susie Gear","doi":"10.1681/ASN.0000001106","DOIUrl":"10.1681/ASN.0000001106","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":"2062-2064"},"PeriodicalIF":9.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147513159","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}