Kidney international最新文献

Gene signature-guided drug screening identified narciclasine as a potential therapeutic for interstitial fibrosis of the kidney.

IF 19.6 1区医学

Kidney international Pub Date : 2025-04-22 DOI: 10.1016/j.kint.2025.03.021

An Xiao,Xiaoer Chen,Jingyi Ma,Xiaomei Chen,Tantan Long,Yuanyuan Ma,Qingzhou Chen,Zhiyuan Su,Zheng Hu,Liling Xie,Lei Zhang,Fengxin Zhu,Jing Nie

{"title":"Gene signature-guided drug screening identified narciclasine as a potential therapeutic for interstitial fibrosis of the kidney.","authors":"An Xiao,Xiaoer Chen,Jingyi Ma,Xiaomei Chen,Tantan Long,Yuanyuan Ma,Qingzhou Chen,Zhiyuan Su,Zheng Hu,Liling Xie,Lei Zhang,Fengxin Zhu,Jing Nie","doi":"10.1016/j.kint.2025.03.021","DOIUrl":"https://doi.org/10.1016/j.kint.2025.03.021","url":null,"abstract":"INTRODUCTIONChronic Kidney Disease (CKD) is marked by progressive tubulointerstitial fibrosis (TIF), a pathological feature insufficiently addressed by existing therapies.METHODSTo identify drugs with potential to halt TIF progression, we constructed a TIF-specific gene expression signature using published human CKD kidney transcriptome data and employed the small molecule perturbant library LINCS L1000 database for a high-throughput screening of compounds capable of reversing the expression of TIF-related genes.RESULTSNarciclasine, a natural compound derived from the Narcissus (amaryllis) plant, was identified as a top compound which significantly reversed the gene expression signature of TIF. Administration of narciclasine not only significantly prevented inflammation and fibrotic lesions induced by unilateral ureteral obstruction and unilateral ischemia-reperfusion injury but also delayed the progression of established TIF induced by unilateral ureteral obstruction. Furthermore, in 5/6 nephrectomy induced CKD model, narciclasine significantly lowered serum creatinine, reduced proteinuria, alleviated TIF and inflammation.CONCLUSIONSMechanistically, narciclasine reversed the failed-repair phenotype of tubular epithelial cells and inhibited fibroblasts proliferation and activation, at least partially via inhibiting the activation of NF-κB signaling. Our findings suggest that narciclasine should be further investigated as a promising drug candidate to attenuate CKD.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"5 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876490","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}

引用次数: 0

Targeted delivery of IL-21 neutralizing nanotherapeutics to lymph nodes and kidney allografts attenuates B cell alloimmunity.

IF 19.6 1区医学

Kidney international Pub Date : 2025-04-21 DOI: 10.1016/j.kint.2025.03.017

Hengcheng Zhang,Gianmarco Sabiu,Sungwook Jung,Manuel A Podestà,Jing Zhao,Maya Gempler,Minako Yamamura,Jinxu Miao,George C Tsokos,Ahmad Karadagi,Tatsuo Kawai,Reza Abdi,Peter T Sage

{"title":"Targeted delivery of IL-21 neutralizing nanotherapeutics to lymph nodes and kidney allografts attenuates B cell alloimmunity.","authors":"Hengcheng Zhang,Gianmarco Sabiu,Sungwook Jung,Manuel A Podestà,Jing Zhao,Maya Gempler,Minako Yamamura,Jinxu Miao,George C Tsokos,Ahmad Karadagi,Tatsuo Kawai,Reza Abdi,Peter T Sage","doi":"10.1016/j.kint.2025.03.017","DOIUrl":"https://doi.org/10.1016/j.kint.2025.03.017","url":null,"abstract":"INTRODUCTIONAntibody-mediated rejection (ABMR) after allogeneic kidney transplantation is a substantial clinical problem for which there are no specific treatments. High endothelial venules (HEV) are specialized veins which are normally present only in lymph nodes (LN) facilitating immune cell entry. Here, we show that kidneys undergoing rejection develop HEV-like structures derived from host cells.METHODSWe developed a nano-delivery system targeting HEVs to simultaneously deliver therapeutics to draining LN and kidney allografts.RESULTSUsing this system, we preferentially delivered IL-21 neutralizing antibody (NP-HEV[ aIL21] ) to draining LN and kidney allografts resulting in improved graft function and recipient survival. The NP-HEV[aIL21] system also decreased alloreactive B cell responses, donor-specific antibody production, and ABMR-like lesions in kidney grafts.CONCLUSIONOur study provides a therapeutic strategy to selectively target distinct effector sites to attenuate B-cell alloimmunity while limiting effects of broad systemic immunosuppression in kidney transplantation.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"48 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872117","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}

引用次数: 0

CRISPR-Cas9 mediated proteinase 3 autoantigen deletion as a treatment strategy for anti-neutrophil cytoplasmic autoantibody-associated vasculitis.

IF 19.6 1区医学

Kidney international Pub Date : 2025-04-21 DOI: 10.1016/j.kint.2025.03.020

Uwe Jerke,Claudia Eulenberg-Gustavus,Dimitrios Laurin Wagner,Adrian Schreiber,Ralph Kettritz

{"title":"CRISPR-Cas9 mediated proteinase 3 autoantigen deletion as a treatment strategy for anti-neutrophil cytoplasmic autoantibody-associated vasculitis.","authors":"Uwe Jerke,Claudia Eulenberg-Gustavus,Dimitrios Laurin Wagner,Adrian Schreiber,Ralph Kettritz","doi":"10.1016/j.kint.2025.03.020","DOIUrl":"https://doi.org/10.1016/j.kint.2025.03.020","url":null,"abstract":"INTRODUCTIONProteinase 3 (PR3) is a major autoantigen in patients with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). Here, we performed a proof-of-principle study using ex vivo CRISPR-Cas9 guided gene editing to eliminate the PR3 autoantigen as an alternative to suppressing the autoimmune response to PR3.METHODSA ribonucleoprotein (RNP) complex of Cas9 protein and a PR3-specific single guide-RNA was transfected into human CD34+ hematopoietic stem and progenitor cells (HSPC) by electroporation. Effects on PR3 protein abundance, neutrophil differentiation, and ANCA-dependent and -independent neutrophil responses were assessed.RESULTSGene editing introduced a frame shift in exon 2 of PRTN3. Consequently, PR3 protein was efficiently reduced in neutrophil-differentiated HSPCs as demonstrated by immunoblotting, ELISA, microscopy, and the complete absence of PR3-specific proteolytic activity. Human neutrophil elastase served as control and was not affected. PR3-deleted (PR3KO)- and PR3 wild-type (PR3WT)-HSPCs showed similar neutrophil differentiation. Importantly, general neutrophil defense functions to non-ANCA receptor-independent and -dependent stimuli were similar in PR3KO- and PR3WT-neutrophils as was constitutive apoptosis. Flow cytometry showed that cell membrane-PR3 was significantly reduced on PR3KO-neutrophils and consequent neutrophil activation to either monoclonal antibodies to PR3 or human PR3-ANCA was attenuated. In contrast, myeloperoxidase-ANCA stimulation was not affected.CONCLUSIONSWe show the feasibility and efficacy of depleting the PR3 autoantigen in human CD34+ HSPCs using CRISPR-Cas9. Depleting the PR3 autoantigen instead of suppressing the autoimmune response to PR3 could potentially lead to drug-free remission, particularly in patients with refractory or relapsing disease.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"1075 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872012","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}

引用次数: 0

Single-cell analysis of proximal tubular cells with different DNA content reveals functional heterogeneity in the acute kidney injury to chronic kidney disease transition.

IF 19.6 1区医学

Kidney international Pub Date : 2025-04-21 DOI: 10.1016/j.kint.2025.03.025

Fugang Li,Qigang Lan,Yaqin Wang,Jiachuan Xiong,Tangli Xiao,Shuiqin Gong,Yan Li,Shaobo Wang,Mengying Yao,Liangjing Lv,Shaozong Qin,Wang Xin,Li Liu,Bo Zhang,Jinghong Zhao

{"title":"Single-cell analysis of proximal tubular cells with different DNA content reveals functional heterogeneity in the acute kidney injury to chronic kidney disease transition.","authors":"Fugang Li,Qigang Lan,Yaqin Wang,Jiachuan Xiong,Tangli Xiao,Shuiqin Gong,Yan Li,Shaobo Wang,Mengying Yao,Liangjing Lv,Shaozong Qin,Wang Xin,Li Liu,Bo Zhang,Jinghong Zhao","doi":"10.1016/j.kint.2025.03.025","DOIUrl":"https://doi.org/10.1016/j.kint.2025.03.025","url":null,"abstract":"INTRODUCTIONProximal tubular epithelial cells with different DNA contents emerge after acute kidney injury (AKI). However, their heterogeneity and roles in the acute kidney injury-to-chronic kidney disease (AKI-to-CKD) transition remain incompletely understood.METHODSProximal tubular epithelial cells with different DNA contents were isolated at days 3 and 14 post-AKI following ischemia reperfusion injury for single-cell RNA sequencing.RESULTSHere, we found that proximal tubular epithelial cells with different DNA contents have existing and distinct bulk transcriptome profiles, especially those cells over 4N (polyploid cells with more than four chromosome sets) with upregulated profibrotic signatures. Heterogeneity existed within four distinct functional clusters. In particular, the polyploid cells demonstrated a preferential enrichment within specific proinflammatory and profibrotic clusters post-AKI. Polyploid cells within these specific clusters displayed the profibrotic trajectory, accompanied by increased fibrosis-driving regulon activity and very strong cell-cell interactions. This suggests polyploidy cells have an intrinsic role in promoting the AKI-to-CKD transition. Furthermore, we identified that secreted phosphoprotein 1 (SPP1) as the pivotal hub of polyploid cells and may be involved in various profibrotic signaling pathways. Genetic knockdown of SPP1 in the proximal tubule in vivo dramatically ameliorated kidney fibrosis.CONCLUSIONSOverall, our findings reveal the heterogeneity of proximal tubular epithelial cells with different DNA contents and identify intrinsic factors of polyploid cells such as SPP1 expression in promoting kidney fibrosis. Our study provides novel insights into potential therapeutic target of preventing the AKI-to-CKD transition.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"7 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872118","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}

引用次数: 0

B cell-derived exosomal miR-483-5p and its potential role in promoting kidney function loss in IgA nephropathy.

IF 19.6 1区医学

Kidney international Pub Date : 2025-04-21 DOI: 10.1016/j.kint.2025.03.019

Izabella Za Pawluczyk,Jasraj S Bhachu,Jeremy R Brown,Michael Lacey,Chidimma Mbadugha,Kees Straatman,David Wimbury,Haresh Selvaskandan,Jonathan Barratt

{"title":"B cell-derived exosomal miR-483-5p and its potential role in promoting kidney function loss in IgA nephropathy.","authors":"Izabella Za Pawluczyk,Jasraj S Bhachu,Jeremy R Brown,Michael Lacey,Chidimma Mbadugha,Kees Straatman,David Wimbury,Haresh Selvaskandan,Jonathan Barratt","doi":"10.1016/j.kint.2025.03.019","DOIUrl":"https://doi.org/10.1016/j.kint.2025.03.019","url":null,"abstract":"INTRODUCTIONWhile mesangial IgA deposition is the pathognomonic feature of IgA nephropathy (IgAN) the extent of mesangial IgA accumulation does not correlate with the future risk of kidney failure. This has led to the search for other serum factors that may influence clinical outcome. The emergence of microRNAs (miRs) as negative regulators of gene expression and the increasingly recognized role of extracellular miRs in intercellular communication has prompted study of the influence of miRs on inflammatory and scarring pathways in the kidneys.METHODSHere, next generation sequencing and subsequent qPCR validation identified a significant increase in the serum levels of miR-483-5p, largely packaged within exosomes.RESULTSLevels of miR-483-5p in serum exosomes were greatest in those IgAN patients with higher levels of proteinuria who subsequently developed kidney failure. Exosomal miR-483-5p content significantly correlated with numerous soluble isoforms of the tumor necrosis factor (TNF) receptor super family suggesting lymphocytes as a source of the miR-enriched exosomes. In PBMC miR-483- 5p expression was almost exclusively seen in CD19+ lymphocytes. Activation of a human IgA secreting B cell line with soluble TNFR1 induced miR-483-5p synthesis and enrichment within exosomes. Exposure to miR-483-5p-enriched B cell exosomes resulted in a proinflammatory phenotypic change in cultured human collecting duct epithelial cells, likely mediated through suppression of the transcription factor SOCS3. miR-483-5p-enriched exosomes were also present in the urine of patients with IgAN.CONCLUSIONSInteraction of B lymphocyte-derived miR-enriched exosomes with tubular epithelial cells may provide an explanation for the progressive tubulointerstitial scarring and loss of kidney function seen in IgAN.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"14 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872011","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}

引用次数: 0

Analysis of the prespecified FIDELITY pooled patient dataset examined the efficacy and safety of finerenone in patients with an acute change in estimated glomerular filtration rate.

IF 19.6 1区医学

Kidney international Pub Date : 2025-04-21 DOI: 10.1016/j.kint.2025.03.018

Sankar D Navaneethan,Stefan D Anker,Gerasimos Filippatos,Bertram Pitt,Peter Rossing,Luis M Ruilope,Phyllis August,Meike Brinker,Andrea Lage,Luke Roberts,Charlie Scott,Pantelis Sarafidis,,

{"title":"Analysis of the prespecified FIDELITY pooled patient dataset examined the efficacy and safety of finerenone in patients with an acute change in estimated glomerular filtration rate.","authors":"Sankar D Navaneethan,Stefan D Anker,Gerasimos Filippatos,Bertram Pitt,Peter Rossing,Luis M Ruilope,Phyllis August,Meike Brinker,Andrea Lage,Luke Roberts,Charlie Scott,Pantelis Sarafidis,,","doi":"10.1016/j.kint.2025.03.018","DOIUrl":"https://doi.org/10.1016/j.kint.2025.03.018","url":null,"abstract":"INTRODUCTIONThe efficacy and safety of finerenone (a non-steroidal mineralocorticoid receptor antagonist) versus placebo were assessed according to different changes in estimated glomerular filtration rate (eGFR) using data from FIDELITY, a pooled individual-level analysis of two clinical trials.METHODSPatients had chronic kidney disease (eGFR of 25 ml/min/1.73m2 or greater) and type 2 diabetes with optimized renin-angiotensin system blockade. Risk of composite cardiovascular and composite kidney outcomes was analyzed by baseline eGFR change at month one in the total population and by treatment group.RESULTSOf 12,798 patients, 25.1% had a >10% eGFR decline, 31.2% had a >0-10% decline, 26.8% had a 0-10% increase, and 16.8% had a >10% increase after one month of treatment. Factors associated with acute eGFR decline included higher baseline urine albumin-to-creatinine ratio, eGFR, systolic blood pressure, diuretic or beta-blocker use, and finerenone use. Finerenone significantly reduced composite cardiovascular and kidney outcomes overall and had similar beneficial effect across eGFR subgroups of >10% decline, >0-10% decline, 0-10% increase, and >10% increase for composite cardiovascular (hazard ratio [95% Confidence Interval] of 0.74 [0.61-0.90], 0.87 [0.73-1.04], 1.06 [0.87-1.28], and 0.78 [0.61-0.99], respectively) and kidney outcomes (0.67 [0.53-0.85], 0.78 [0.61-1.01], 0.56 [0.40-0.77], and 0.75 [0.50- 1.14], respectively) (P interaction 0.048 and 0.23, respectively). When modeled as a continuous variable, finerenone reduced the risk of cardiovascular and kidney outcomes, irrespective of acute eGFR change (P interaction 0.58 and 0.36 respectively).CONCLUSIONThe cardiovascular and kidney benefits of finerenone were not modified by an acute eGFR change after drug initiation.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"7 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872024","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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IF 14.8 1区医学

Kidney international Pub Date : 2025-04-18 DOI: 10.1016/S0085-2538(25)00238-8

引用次数: 0

Clarifying criteria for complement-mediated TMA in patients without CFH antibodies or complement variants identified

IF 14.8 1区医学

Kidney international Pub Date : 2025-04-18 DOI: 10.1016/j.kint.2025.02.005

Alice Doreille , Laurent Mesnard

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GLP-1 receptor agonists and other incretin mimetics for diabetes and chronic kidney disease—a KDIGO commentary 治疗糖尿病和慢性肾病的 GLP-1 受体激动剂和其他增量素模拟物--KDIGO 评论

IF 14.8 1区医学

Kidney international Pub Date : 2025-04-18 DOI: 10.1016/j.kint.2024.12.019

Ian H. de Boer , M. Luiza Caramori , Juliana C.N. Chan , Hiddo J.L. Heerspink , Kamlesh Khunti , Adrian Liew , Erin D. Michos , Sankar D. Navaneethan , Wasiu A. Olowu , Tami Sadusky , Nikhil Tandon , Katherine R. Tuttle , Christoph Wanner , Katy G. Wilkens , Sophia Zoungas , Peter Rossing

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Progress, challenges, and pragmatic concessions in predicting relative risk of kidney survival in ARPKD

IF 14.8 1区医学

Kidney international Pub Date : 2025-04-18 DOI: 10.1016/j.kint.2025.02.018

Derek K. Ng , Matthew B. Matheson , Erum A. Hartung

引用次数: 0