Journal of The American Society of Nephrology最新文献

{"title":"Alternative Splicing in Mechanically Stretched Podocytes as a Model of Glomerular Hypertension.","authors":"Francescapaola Mattias, Olga Tsoy, Elke Hammer, Alexander Gress, Stefan Simm, Chit Tong Lio, Sabine Ameling, Kerstin Amann, Leonie Dreher, Ulrich Wenzel, Tim Kacprowski, Markus List, Olga Kalinina, Karlhans Endlich, Jan Baumbach, Uwe Völker, Nicole Endlich, Felix Kliewe","doi":"10.1681/ASN.0000000706","DOIUrl":"10.1681/ASN.0000000706","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144150939","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":"mTOR Inhibitors and Vaccine Response in Kidney Transplant Recipients.","authors":"Griffith B Perkins,Matthew J Tunbridge,Cheng Sheng Chai,Christopher M Hope,Arthur Eng Lip Yeow,Tania Salehi,Julian Singer,Bree Shi,Makutiro G Masavuli,Zelalem Addis Mekonnen,Pablo Garcia-Valtanen,Svjetlana Kireta,Julie K Johnston,Christopher J Drogemuller,Beatrice Z Sim,Shane M Spencer,Benedetta C Sallustio,Iain Comerford,George Bouras,Daniela Weiskopf,Alessandro Sette,Anupriya Aggarwal,Vanessa Milogiannakis,Anouschka Akerman,Stuart Turville,Plinio R Hurtado,Tracey Ying,Pravin Hissaria,Simon C Barry,Steven J Chadban,Branka Grubor-Bauk,P Toby Coates","doi":"10.1681/asn.0000000716","DOIUrl":"https://doi.org/10.1681/asn.0000000716","url":null,"abstract":"BACKGROUNDFailure to develop protective immunity in response to vaccination is common among kidney transplant recipients, rendering them susceptible to severe infection. Novel strategies are required. Here, we investigated the potential of mechanistic-target-of-rapamycin (mTOR) inhibitors to improve vaccine responses.METHODSHumoral and cellular responses to primary COVID-19 vaccination (ChAdOx1 or BNT162b2) were assessed for kidney transplant recipients receiving mTOR inhibitor-based (mTOR inhibitor, mycophenolate, prednisolone, N=15) and standard-of-care (tacrolimus, mycophenolate, prednisolone, N=40) immunosuppression, and healthy cohabitants (N=71), in a prospective observational study. Findings were validated and mechanisms explored in mice. Low/non-responding kidney transplant recipients receiving standard-of-care immunosuppression (N=54) were then randomized 1:1 to switch from mycophenolate to sirolimus, or remain on standard-of-care, for 4 weeks prior to receiving COVID-19 booster vaccination. Augmentation of immunity to COVID-19 was assessed as the primary outcome measure.RESULTSA 12-fold greater IFNγ-T cell response to primary vaccination was observed in kidney transplant recipients receiving mTOR inhibitor-based versus standard-of-care immunosuppression (520 vs 43 spot-forming units/106 cells, p < 0.001). A greater frequency of functional memory T cells in the mTOR inhibitor group was observed for both the CD4+ (0.20% vs. 0.05%, p < 0.001) and CD8+ (0.35% vs. 0.07%, p = 0.006) compartments by flow cytometry, and kidney transplant recipients receiving mTOR inhibitor-based immunosuppression produced greater frequencies of SARS-CoV-2-specific CD4+ T cells than healthy cohabitants (1.17% vs 0.48%, p = 0.03). In mice, sirolimus treatment enhanced both recall and de novo T cell responses to homologous and Omicron-specific booster vaccines. Switch from mycophenolate to sirolimus was well tolerated, however no significant difference was observed in the proportion of kidney transplant recipients in the intervention and control arms that achieved protective virus neutralization (10/25 [40%] vs 9/21 [43%] respectively, p = 0.85), nor in T cell response to vaccination (p = 0.89).Conclusions: mTOR inhibition was associated with improved T cell memory formation in kidney transplant recipients, however this effect was not reproduced by a short-term mycophenolate to sirolimus switch strategy.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"33 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122022","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":"Expanding the Implications of Proximal Tubular Function Assessment.","authors":"Chia-Ter Chao","doi":"10.1681/asn.0000000743","DOIUrl":"https://doi.org/10.1681/asn.0000000743","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"18 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114230","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":"RNA Alternative Splicing and Polyadenylation and Regulation of the Glomerular Filtration Barrier.","authors":"Monoj K Das, Amy Webb, Mahika Yarram, Christian Reilly, Lalith Punepalle, Claire Bryant, Rajgopal Govindarajan, Claire L Moore, Shipra Agrawal","doi":"10.1681/ASN.0000000748","DOIUrl":"10.1681/ASN.0000000748","url":null,"abstract":"<p><strong>Background: </strong>Glomerular disease, characterized by podocyte injury and proteinuria, can lead to CKD and end-stage kidney disease. We hypothesized that the glomerular pathophysiology is associated with mRNA alternative splicing and polyadenylation of glomerular genes and of critical podocyte and slit diaphragm components that regulate the filtration barrier.</p><p><strong>Methods: </strong>Glomerular damage, accompanied by proteinuria, was induced by puromycin-aminonucleoside or adriamycin to mimic human minimal change disease or FSGS, respectively, and RNA-seq analyses was performed. Alternatively spliced and polyadenylated events through differential exon and poly(A) site usage were queried in JunctionSeq and APATrap pipelines. These events were further mapped on podocyte and glomerular landscape, analyzed and modulated for slit diaphragm components, and cis- and trans-regulatory elements were identified.</p><p><strong>Results: </strong>Altered glomerular mRNA processing by alternative splicing/polyadenylation was identified in 136/71 and 1875/746 genes in minimal change disease and FSGS models, respectively. Transcript annotation and prioritization of significant alternative splicing and polyadenylation identified key events in several podocyte and slit diaphragm genes with novel and established roles. Alternative splicing of critical slit diaphragm components, the junction protein TJP1/ZO1 and microtubule associating protein ITM2B was further characterized. Alternative polyadenylation of core members of the slit diaphragm, NPHS1 , NPHS2 and NEPH1 was analyzed with potential alteration of microRNA binding sites between the proximal vs distal poly (A) site usage in their mRNAs. Concomitantly, dysregulation of trans-regulatory elements (polyadenylation and splicing factors), was discovered in these models of nephropathies. Additionally, beneficial proteinuria-reducing treatments, pioglitazone and GQ16 reversed many alternatively spliced and polyadenylated events. Moreover, GWAS SNPs as potential cis-regulatory elements were identified in several genes from the human nephrotic syndrome database. Finally, we demonstrated proof-of-concept principle of chemically modified splice switching oligonucleotides in modulating TJP1 splicing in podocytes.</p><p><strong>Conclusions: </strong>Findings from our studies identified that glomerular pathophysiology and disruption of the filtration barrier is associated with alternative splicing and polyadenylation of glomerular genes, many of which are crucial determinants of podocyte structure and function and the slit diaphragm complex.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120083","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":"Authors' Reply: Expanding the Implications of Proximal Tubular Function Assessment.","authors":"Bernardo Rodriguez-Iturbe,Ana Karen Fernández-Yepez,Magdalena Madero","doi":"10.1681/asn.0000000744","DOIUrl":"https://doi.org/10.1681/asn.0000000744","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"135 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114228","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":"Voclosporin Overdose-Induced Peroxisomal Structural Changes and AKI Are Prevented by Renal Indole Detoxifier, INMT.","authors":"Kazuhiro Hasegawa,Yusuke Sakamaki,Masanori Tamaki,Shu Wakino","doi":"10.1681/asn.0000000751","DOIUrl":"https://doi.org/10.1681/asn.0000000751","url":null,"abstract":"BACKGROUNDThe novel calcineurin inhibitor (CNI) voclosporin is effective in treating lupus nephritis but has been associated with acute kidney injury (AKI) through largely unknown mechanisms. Voclosporin-induced AKI revealed that voclosporin reduces the expression of indolethylamine N-methyltransferase (Inmt), an enzyme responsible for detoxifying local uremic toxins such as indole. This study investigates whether Inmt overexpression can protect against high-dose voclosporin-induced AKI. This study used genetically engineered mice to explore the role of Inmt in voclosporin-induced AKI.METHODSTransgenic mice overexpressing Inmt and conditional knockout (conditional KO) mouse models were used assess renal proximal tubule-specific Inmt function. Gene expression changes, apoptotic cell percentages, and mitochondrial DNA copy numbers were examined through RNA sequencing, histopathology, and various molecular assays. These analyses were further complemented with immunofluorescence and electron microscopy to investigate cellular and structural changes. Human clinical specimens were also investigated.RESULTSInmt downregulation in high-dose voclosporin-induced AKI was associated with reduced peroxisome and mitochondrion numbers and function, increased production of reactive oxygen species, and increased tubular apoptosis, as observed in conditional KO mice. However, in transgenic mice treated with voclosporin, peroxisomal and mitochondrial integrity were preserved. Notably, electron microscopy revealed that the structural peroxisomal changes observed in mouse and human CNI-induced AKI specimens were reversed in high-dose voclosoprin-treated transgenic mice. Overall, proximal tubule-specific Inmt overexpression protects against high-dose voclosporin-induced AKI by promoting catalase upregulation, reducing H2O2 levels, and restoring peroxisomal function.CONCLUSIONSInmt overexpression in proximal tubules prevented high-dose voclosporin-induced structural changes and AKI.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"31 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114231","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":"mTORc1 in Distal Convoluted Tubule (DCT) and Renal Potassium (K+) Handling.","authors":"Yu Xiao,Xin-Peng Duan,Cheng-Biao Zhang,Wen-Hui Wang,Dao-Hong Lin","doi":"10.1681/asn.0000000727","DOIUrl":"https://doi.org/10.1681/asn.0000000727","url":null,"abstract":"BACKGROUNDMechanistic-target-of-rapamycin-complex-1 (mTORc1) plays a role in maintaining K+ homeostasis. We now examine whether mTORc1 of distal-convoluted-tubule (DCT) regulates Kir4.1/Kir5.1 channels and thiazide-sensitive-Na-Cl cotransporter, which plays a role in regulating renal K+ excretion.METHODSWe used patch-clamp-technique to examine basolateral Kir4.1/Kir5.1 in early-DCT, immunoblotting to examine NCC expression and in vivo measurement of urinary K+-excretion to determine baseline renal K+-excretion (EK) in the mice treated with rapamycin and in DCT-specific regulatory-associated-protein-of-mechanisticc-target-of-rapamycin knockout mice (DCT-RAPTOR-KO).RESULTSApplication of rapamycin decreased Kir4.1/Kir5.1-mediated K+-currents and depolarized DCT-membrane-potential in Fkbp1aflox/flox mice. However, the effect of rapamycin on Kir4.1/Kir5.1 was absent in kidney-specific-FKBP12-knockout mice (Ks-FKBP12-KO). Rapamycin decreased basolateral 40-pS K+-channel activity (Kir4.1/Kir5.1 heterotetramer) of the DCT. This effect was absent in the DCT treated with H2O2 which stimulated the 40-pS K+-channel activity, suggesting the role of reactive-oxygen-species (ROS) in mediating the effect of mTORc1 on Kir4.1/Kir5.1. Rapamycin treatment significantly decreased the abundance of both phosphorylated-NCC and total-NCC in Fkbp1aflox/flox mice but not in Ks-FKBP12-KO mice. Moreover, in vivo measurement of urinary Na+-excretion and urinary K+-excretion demonstrated that rapamycin treatment decreased hydrochlorothiazide-induced natriuresis but increased renal K+-excretion in Fkbp1aflox/flox mice. Moreover, Kir4.1/Kir5.1 mediated K+-currents of the DCT were lower and DCT membrane potential was less negative in DCT-RAPTOR-KO than those of Ncc-Cre-Raptorflox/flox mice. Also, the abundance of phosphorylated-NCC was lower in DCT-RAPTOR-KO mice than Ncc-Cre-Raptorflox/flox mice. In contrast, the abundance of phosphorylated-NKCC2 was the same between two genotypes while cleaved αENaC abundance was higher in DCT-RAPTOR-KO mice than Ncc-Cre-Raptorflox/flox mice. Consequently, DCT-RAPTOR-KO mice had a higher urinary K+-excretion and lower plasma K+ concentrations than Ncc-Cre-Raptorflox/flox.Conclusions: mTORc1 in the DCT plays a significant role in maintaining K+ homeostasis by controlling the basolateral Kir4.1/Kir5.1 of the DCT and NCC.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"3 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114229","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":"Hypercalcemia's Hidden Regulator: Calcium-Sensing Receptor and the Kidney's Secret Weapon.","authors":"Jessica Paola Bahena-López,Gerardo Gamba","doi":"10.1681/asn.0000000725","DOIUrl":"https://doi.org/10.1681/asn.0000000725","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"42 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065580","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":"Evidence-Based Guidance for Strategies for Blood Transfusion with CKD and Myocardial Infarction.","authors":"Michelle M Y Wong,Charles A Herzog","doi":"10.1681/asn.0000000736","DOIUrl":"https://doi.org/10.1681/asn.0000000736","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"35 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945471","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":"Safety and Efficacy of Vadadustat for the Treatment of CKD-Related Anemia within and outside the United States.","authors":"Glenn M Chertow,Kai-Uwe Eckardt,Mark J Sarnak,Wolfgang C Winkelmayer,Rajiv Agarwal,Todd Minga,Wenli Luo,Steven K Burke","doi":"10.1681/asn.0000000708","DOIUrl":"https://doi.org/10.1681/asn.0000000708","url":null,"abstract":"BACKGROUNDVadadustat's global clinical program was comprised of four noninferiority trials comparing vadadustat and darbepoetin alfa for CKD-related anemia: two in dialysis-dependent (DD)-CKD and two in non-dialysis-dependent (NDD)-CKD. While vadadustat met prespecified noninferiority criteria for hematological efficacy globally, it did not meet noninferiority criteria for cardiovascular safety in the NDD-CKD trials. The trials considered regional differences in treatment practices, including hemoglobin targets within (10-11 g/dL) and outside the US (10-12 g/dL).METHODSTo examine region-specific outcomes, we performed prespecified analyses for US and non-US patient subgroups from the vadadustat global program. The primary safety end point was first occurrence of MACE (death from any cause, or nonfatal myocardial infarction or stroke). The primary efficacy end point was change in hemoglobin from baseline to average values during weeks 24-36.RESULTS4084/7399 (55%) randomized patients were enrolled in the US. In pooled analyses of all US patients, MACE risk was similar among vadadustat-treated and darbepoetin alfa-treated patients (hazard ratio [HR] 1.03; 95% CI 0.90-1.17). HRs were similar for US patients with DD-CKD (HR 1.00; 95% CI 0.84-1.18) and NDD-CKD (HR 1.06; 95% CI 0.87-1.29). In pooled analyses of non-US patients, MACE risk was numerically higher among vadadustat-treated patients (HR 1.12; 95% CI 0.94-1.33); the higher risk was primarily attributed to the NDD-CKD subgroup (HR 1.29; 95% CI 1.03-1.60). In the non-US DD-CKD subgroup, MACE risk was similar among vadadustat-treated and darbepoetin alfa-treated patients (HR 0.88; 95% CI 0.67-1.17). Changes in hemoglobin were similar among treatment groups in all regions, as were rates of treatment-emergent and serious adverse events.CONCLUSIONSIn patients with DD-CKD, safety (vis-à-vis MACE) and efficacy (vis-à-vis change in hemoglobin) of vadadustat and darbepoetin alfa were similar when stratified by region (US versus non-US). In US patients with NDD-CKD, safety and efficacy of vadadustat and darbepoetin alfa were similar.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"32 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945473","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}