Journal of The American Society of Nephrology最新文献

{"title":"Numerical Flow Simulations of the Shear Stress Forces Arising in Filtration Slits during Glomerular Filtration in Rat Kidney.","authors":"Alexander Fuhrmann, Balazs Pritz, Karlhans Endlich, Wilhelm Kriz","doi":"10.1681/ASN.0000000513","DOIUrl":"https://doi.org/10.1681/ASN.0000000513","url":null,"abstract":"<p><strong>Background: </strong>The flow dynamic forces during glomerular filtration challenging the fixation of podocytes to the GBM are insufficiently understood.</p><p><strong>Methods: </strong>Numerical flow simulations were used to estimate these forces in the rat kidney. Simulations were run with a 3D model of the slit diaphragm as a zipper structure according to Rodewald and Karnovsky 1. The GBM was modeled as a porous medium.</p><p><strong>Results: </strong>Filtrate flow exerted a mean wall shear stress of 39 Pa with a maximum of 152 Pa on the plasma membrane of foot processes and up to 250 Pa on internal surfaces of the slit diaphragm. The slit diaphragm accounted for 25% of the hydrodynamic resistance of the glomerular filtration barrier. Based on the results of the 3D model, we developed a 2D model that allowed us to perform extensive parameter variations. Reducing the filtration slit width from 40 to 30 nm almost doubled wall shear stress. Furthermore, increasing filtrate flow velocity by 50% increased wall shear stress by 47%. When increasing the viscous resistance of the slit diaphragm, the pressure drop across the slit diaphragm increased to intolerably high values. A lower viscous resistance of the slit diaphragm than that of the GBM accounted for a gradual pressure decline along the filtration barrier. The sub-podocyte space tempered these challenges in circumscribed areas of filtration surface but had only a marginal impact on overall forces.</p><p><strong>Conclusions: </strong>The filtration barrier experiences high levels of shear and pressure stress accounting for the detachment of injured but viable podocytes from the GBM--a hallmark in many glomerular diseases.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142349098","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":"Treating the Untreatable: Antisense Oligonucleotides as an Individualized Therapy for Rare Genetic Kidney Disease.","authors":"Cedrik Tekendo-Ngongang,Joseph G Gleeson,Laurence Mignon","doi":"10.1681/asn.0000000532","DOIUrl":"https://doi.org/10.1681/asn.0000000532","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"7 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329261","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":"Damage-Associated Molecular Patterns and Pattern Recognition Receptors in the Podocyte.","authors":"Robert L Myette,Mayra Trentin-Sonoda,Chloé Landry,Chet E Holterman,Tony Lin,Dylan Burger,Christopher R J Kennedy","doi":"10.1681/asn.0000000531","DOIUrl":"https://doi.org/10.1681/asn.0000000531","url":null,"abstract":"Podocytes possess immune system components allowing for a variety of innate responses to endogenous and exogenous stimuli. Recently, several groups have linked inappropriate innate immune signaling to podocyte injury, particularly chronic, sustained injury; however, the immune capabilities of podocytes have not been fully elucidated. Damage associated molecular patterns (DAMPs) are endogenous danger molecules released from damaged cells, including podocytes, and can elicit an inflammatory response and recruit immune cells to areas of injury. This is done through binding to pattern recognition receptors (PRR). Thought largely to be protective and responsive to injury or infection, recent evidence suggests signaling via DAMP pathways can aggravate and promote chronic diseases already associated with inflammation. The purpose of this narrative review is to highlight current knowledge with respect to specific podocyte DAMPs and PRRs, and to provide insight into ongoing work and possible future research avenues to advance our understanding of podocyte immune mechanisms.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"53 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329256","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":"Learning from Negative Trials for Diabetic Kidney Disease.","authors":"Rhian M Touyz","doi":"10.1681/asn.0000000511","DOIUrl":"https://doi.org/10.1681/asn.0000000511","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"281 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328769","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":"Functional Characterization of Anti-C3bBb Autoantibodies and C3 Glomerulopathy Phenotype.","authors":"Julia Roquigny,Marie-Sophie Meuleman,Carine El Sissy,Mathilde Cailliez,Aude Servais,Gwenaelle Roussey,Véronique Baudouin,Stéphane Decramer,François Nobili,Alain Wynckel,Anne-Laure Sellier Leclerc,Anne-Laure Lapeyraque,Paula Vieira Martins,Seppo Meri,Marie-Agnès Dragon-Durey,Sophie Chauvet,Véronique Frémeaux-Bacchi","doi":"10.1681/asn.0000000000000499","DOIUrl":"https://doi.org/10.1681/asn.0000000000000499","url":null,"abstract":"BACKGROUNDC3 nephritic factors, i.e. autoantibodies that stabilize the C3 convertase of the alternative pathway are the most frequent acquired abnormality in C3 glomerulopathy and primary immunoglobulin-mediated membranoproliferative GN (Ig-MPGN).METHODSOur study included 27 patients with C3 glomerulopathy (n=21) or Ig-MPGN (n=6), of whom 78% were children at disease onset. At the time of sampling, 13/19 (68%) patients with low C3 levels and 8/8 (100%) patients with normal C3 levels were positive for C3 nephritic factors by haemolytic assay. Using novel Luminex assays, we performed a screening for IgG that recognize and affect the formation and/or the stabilization of the alternative pathway C3 convertase (C3bBb).RESULTSUsing Luminex assays, an increase in C3bBb formation and/or stabilization was observed in the presence of IgG from 18/27 patients, including 9 with a double-function, 6 only enhancing the C3bBb formation, and 3 that exclusively stabilized C3bBb. All patients presenting a formation and stabilization function had a low C3 level, versus 55% without this double-function. The level of C3bBb formation correlated to the plasmatic C3 but not sC5b-9 levels. The stabilization of C3bBb did not correlate with C3 or sC5b-9 levels. At the last follow-up, 5/27 patients (19%) reached kidney failure after a median delay of 87 [52,119] months. The patients positive for double-function anti-C3bBb antibodies had a 5-year kidney survival of 70% compared to 100% in those negative (P=0.02).CONCLUSIONSOur findings highlight the association of the dual function of C3bBb formation and stabilization with severe C3 consumption and poor kidney survival in C3 glomerulopathy and Ig-MPGN.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"30 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328767","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":"Systematic Screening of ADTKD-MUC1 27dupC Pathogenic Variant through Exome Sequencing.","authors":"Ilias Bensouna,Thomas Robert,Xavier Vanhoye,Marine Dancer,Laure Raymond,Pierre Delaugère,Pascale Hilbert,Hugues Richard,Laurent Mesnard","doi":"10.1681/asn.0000000503","DOIUrl":"https://doi.org/10.1681/asn.0000000503","url":null,"abstract":"BACKGROUNDThe MUC1 gene is associated with autosomal dominant tubulointerstitial kidney disease (ADTKD), leading to CKD. Current methods of sequencing, like exome sequencing, rarely detect MUC1 pathogenic variants because of the variable number of tandem repeats (VNTR) in MUC1 exon2. We demonstrated that combining fast read filtering with a sensitive VNTR genotyping strategy enables systematic screening of 27dupC pathogenic MUC1 variant from exome data.METHODSWe initially validated our bioinformatics pipeline in a proof-of-concept cohort incorporating exome data from 33 participants with a known MUC1 pathogenic variant identified by Snapshot PCR and confirmed by 54 MUC1-negative individuals for negative control. We then retrospectively analyzed exome sequencing data from January 2019 to October 2023 from 3512 adult participants with nephropathy of unknown origin. Finally, we prospectively validated our pipeline in 825 additional participants enrolled from November 2023.RESULTSSharkVNTyper accurately identified MUC1 variants in 32 out of 33 participants and excluded its presence in all the 54 negative controls in the proof-of-concept cohort (sensitivity of 97%, specificity of 100%). Integration of Shark tool with VNTyper significantly reduced running time from 6-12 hours to 5-10 minutes per sample, allowing both retrospective and prospective analysis. In the retrospective cohort, SharkVNTyper identified 23 additional positive cases that were not suspected clinically and had been missed in the initial exome analysis; 18 of these cases were confirmed as carrying the MUC1 27dupC mutation by low-throughput Snapshot PCR. In the prospective cohort of 825 CKD cases, systematic screening discovered 13 positive cases, with 12 confirmed by PCR. Overall, of 63 participants (1.4% of 4653) with molecularly confirmed ADTKD-MUC1, comprehensive diagnoses and descriptions of the disease were available for 24 participants. Median age of kidney failure was 50 years, 38% exhibited bilateral multiple kidney cysts, 8% had early-onset gout, and 58% had arterial hypertension.CONCLUSIONSSharkVNTyper enables the analysis of highly repeated regions, such as the MUC1 VNTR, and facilitates the systematic screening of ADTKD-MUC1 from exome data, fostering 27dupC variation identification.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"8 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328844","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":"Proteomic Assessment of the Risk of Secondary Cardiovascular Events among Individuals with CKD.","authors":"Rajat Deo,Ruth F Dubin,Yue Ren,Jianqiao Wang,Harold Feldman,Haochang Shou,Josef Coresh,Morgan E Grams,Aditya L Surapaneni,Jordana B Cohen,Mayank Kansal,Mahboob Rahman,Mirela Dobre,Jiang He,Tanika Kelly,Alan S Go,Paul L Kimmel,Ramachandran S Vasan,Mark R Segal,Hongzhe Li,Peter Ganz","doi":"10.1681/asn.0000000502","DOIUrl":"https://doi.org/10.1681/asn.0000000502","url":null,"abstract":"BACKGROUNDCardiovascular risk models have been developed primarily for incident events. Well-performing models are lacking to predict secondary cardiovascular events among people with a history of coronary heart disease, stroke, or heart failure who also have chronic kidney disease (CKD). We sought to develop a proteomics-based risk score for cardiovascular events in individuals with CKD and a history of cardiovascular disease.METHODSWe measured 4638 plasma proteins among 1067 participants from the Chronic Renal Insufficiency Cohort (CRIC) and 536 individuals from the Atherosclerosis Risk in Communities Cohort (ARIC). All had non-dialysis-dependent CKD and coronary heart disease, heart failure, or stroke at study baseline. A proteomic risk model for secondary cardiovascular events was derived by elastic net regression in CRIC, validated in ARIC, and compared to clinical models. Biologic mechanisms of secondary events were characterized through proteomic pathway analysis.RESULTSA 16-protein risk model was superior to the Framingham risk score for secondary events, including a modified score that included estimated glomerular filtration rate (eGFR). In CRIC, the annualized area under the receiver operating characteristic (AUC) within 1 to 5 years ranged between 0.77 and 0.80 for the protein model and 0.57 and 0.72 for the clinical models. These findings were replicated in the ARIC validation cohort. Biologic pathway analysis identified pathways and proteins for cardiac remodeling and fibrosis, vascular disease, and thrombosis.CONCLUSIONSThe proteomic risk model for secondary cardiovascular events outperformed clinical models based on traditional risk factors and eGFR.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"76 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328766","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":"Long Shadows: Understanding the Lifelong Risk of Acute Kidney Injury in Childhood.","authors":"Emily J See,Catherine Quinlan","doi":"10.1681/asn.0000000508","DOIUrl":"https://doi.org/10.1681/asn.0000000508","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"49 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324952","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":"Posoleucel for BK Polyomavirus in Kidney Transplant Recipients.","authors":"Maud Wilhelm,Anne Geng,Stefan Schaub,Hans H Hirsch","doi":"10.1681/asn.0000000000000500","DOIUrl":"https://doi.org/10.1681/asn.0000000000000500","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"190 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142275261","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":"Production of Acetylcholine by Podocytes and its Protection from Kidney Injury in Glomerulonephritis.","authors":"Luan D Truong,Jessica Trostel,Carlos Roncal,Gabriel Cara-Fuentes,Makoto Miyazaki,Shinobu Miyazaki-Anzai,Ana Andres-Hernando,Fumihiko Sasai,Miguel Lanaspa,Richard J Johnson,Gabriela E Garcia","doi":"10.1681/asn.0000000000000492","DOIUrl":"https://doi.org/10.1681/asn.0000000000000492","url":null,"abstract":"BACKGROUNDOne of the most important factors modulating endothelial health is acetylcholine, and while it is associated as a cholinergic neurotransmitter; it is also expressed by non-neuronal cells. However, its role in the kidney, which does not receive cholinergic innervation, remains unknown.METHODSTo determine if acetylcholine is produced in the kidney, we used ChAT(BAC)-eGFP (ChAT mice) transgenic mice in which enhanced green fluorescent protein (eGFP) is expressed under the control of the endogenous choline acetyltransferase (ChAT) transcriptional regulatory elements. We then investigated the role of acetylcholine in kidney disease by inducing anti- glomerular basement membrane glomerulonephritis (anti-GBM GN) in ChAT transgenic mice.RESULTSWe demonstrate ChAT, the sole enzyme responsible for acetylcholine production, was expressed in glomerular podocytes and produced acetylcholine. We also show during anti-GBM GN in ChAT transgenic mice, ChAT expression was induced in the glomeruli, mainly in podocytes and protects mice from kidney injury with marked reduction of glomerular proliferation/fibrinoid necrosis (by 71%) crescent formation (by 98%), and tubular injury (by 78%). In contrast, specific knockout of podocyte ChAT worsened the severity of the disease. The mechanism of protection included reduction of inflammation, attenuation of angiogenic factors reduction, and increase of eNOS expression. In vitro and in vivo studies demonstrated available drugs like cholinesterase inhibitors and ChAT inducers increased the expression of podocyte-ChAT and acetylcholine production.CONCLUSIONSThese findings suggest de novo synthesis of acetylcholine by podocytes protected against inflammation and glomerular endothelium damage in anti-GBM glomerulonephritis.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"16 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142275247","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}