Journal of The American Society of Nephrology最新文献

{"title":"Pathogenesis and Translational Perspectives in Myeloma-Associated Nephropathy.","authors":"Paul W Sanders","doi":"10.1681/ASN.0000001249","DOIUrl":"10.1681/ASN.0000001249","url":null,"abstract":"<p><p>Kidney injury associated with the tubulointerstitial disease that occurs in multiple myeloma is a multifactorial and potentially reversible process that centers on the monoclonal free light chain (FLC). FLCs promote kidney damage through mechanisms that include precipitation with uromodulin to initiate the formation of obstructing casts in the distal nephron and activation and injury to proximal tubule epithelium. These processes generate tubulointerstitial inflammatory and fibrotic pathways that lead to progressive kidney failure if not interrupted. Important predisposing factors include the physicochemical characteristics and the amount of the FLC present in the tubular nephron. Precipitating factors for the two lesions-cast formation and proximal tubulopathy-are also discussed. Current evidence shows that both pathomechanisms can occur independently or synergize to promote kidney failure. This narrative review integrates obstructive cast formation and proximal tubulopathy to consider a unified translational therapeutic approach for myeloma kidney to improve outcomes in this devastating complication of multiple myeloma.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794908","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":"Altered Complement and Tubular Mitochondrial Proteins Are Linked to Graft Loss in DSA + Antibody-Mediated Rejection.","authors":"Kieran P Manion, Maya A Allen, Augusta Vincent, Sergi Clotet-Freixas, Chiara Pastrello, Sofia Farkona, Alex Boshart, Slaghaniya Neupane, Hong Sang Choi, Stella Wang, Ella Huszti, Shenghui Su, Jinguo Wang, Jeffrey Kiernan, Sean Delaney, Sadia Baig, Segun Famure, Yanhong Li, S Joseph Kim, Aniruddh Sarkar, Igor Jurisica, Rohan John, Jishnu Das, Ana Konvalinka","doi":"10.1681/ASN.0000001224","DOIUrl":"10.1681/ASN.0000001224","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Key points: &lt;/strong&gt;DSA + kidney grafts with antibody-mediated rejection had higher glomerular and tubulointerstitial complement protein levels than those with donor-specific antibodies but no rejection. DSA + patients without rejection lacked accommodation but showed preserved podocyte and tubular protein expression compared with antibody-mediated rejection. Elevated complement and decreased mitochondrial proteins were associated with death-censored allograft loss in DSA + patients with antibody-mediated rejection.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Antibody-mediated rejection (AMR) is the main driver of late kidney allograft loss. Anti-HLA donor-specific antibodies (DSAs) are strongly associated with AMR. However, 30%-60% of DSA + patients do not develop AMR, raising the possibility of local tissue adaptations to DSAs.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We performed unbiased proteomic analysis on glomeruli and tubulointerstitium isolated using laser-capture microdissection from the kidney biopsies of 116 DSA + kidney transplant recipients with Banff-classified active AMR, chronic active AMR, mixed AMR, or no rejection. The Significant Latent factor Interaction Discovery and Exploration (SLIDE) machine learning algorithm was used to identify latent factors linked to graft loss among patients with AMR.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We quantified 1917 glomerular and 2758 tubulointerstitial proteins by mass spectrometry, with 127 glomerular and 389 tubulointerstitial proteins significantly differentially expressed between all 4 patient groups (one-way ANOVA P &lt; 0.05, Tukey false discovery rate &lt;0.05). In glomeruli, chronic active AMR had the most differentially expressed proteins, consisting primarily of complement and basement membrane components. Tubulointerstitial terminal complement proteins were also significantly increased in chronic active AMR but did not correlate with C4d deposition. Mixed AMR contained the most differentially expressed proteins in the tubulointerstitium, which were linked to IFNγ-associated immune activation, stress responses, and mitochondrial metabolism. DSA + biopsies without rejection were characterized by preservation of podocyte and tubular proteins in glomeruli and tubulointerstitium, respectively, but did not show conventional markers of accommodation. SLIDE identified 3 latent factors from the glomerular proteome and 4 from the tubulointerstitial proteome that significantly distinguished AMR patients with and without graft loss, correlated significantly with allograft injury, and improved prediction of graft loss beyond standard clinical variables in a multivariable risk model. Top proteins within the glomerular SLIDE model included complement components, while top proteins for the tubulointerstitial SLIDE model included tubular and mitochondrial proteins.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;AMR and graft loss after kidney transplantation were defined by compartment-specific disruptions in complement a","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148759772","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":"Hemodiafiltration versus High-Flux Hemodialysis and Risk of Mortality: A Multinational Target Trial Emulation.","authors":"Giovanni F M Strippoli, Giovanni Tripepi, Bernard Canaud, Stefano Stuard, Franklin W Maddux, Len A Usvyat, Paola Carioni, Matteo Savoia, Germaine Wong, Carmine Zoccali","doi":"10.1681/ASN.0000001225","DOIUrl":"10.1681/ASN.0000001225","url":null,"abstract":"<p><strong>Key points: </strong>Randomized trials suggested that hemodiafiltration improved survival over high-flux hemodialysis, but real-world evidence is limited. Target trial emulation showed that hemodiafiltration was associated with lower mortality than high-flux hemodialysis. The findings supported broader use of hemodiafiltration when technically feasible and clinically appropriate.</p><p><strong>Background: </strong>Randomized trials suggest that high-volume postdilution hemodiafiltration (HDF) may improve survival compared with high-flux hemodialysis, but evidence from routine clinical practice and from regions underrepresented in trials remains limited.</p><p><strong>Methods: </strong>We emulated a target trial comparing HDF with high-flux hemodialysis using data from European Clinical Database, a multinational registry of dialysis patients treated in 8 European countries. Adults receiving thrice-weekly in-center dialysis between 2014 and 2019 were eligible. Follow-up began 91 days after dialysis initiation. Sustained treatment strategies were defined as receipt of the assigned modality for at least 90% of sessions. Inverse probability weighting was used to emulate randomized treatment assignment. The primary outcome was all-cause mortality, with kidney transplantation treated as a competing event.</p><p><strong>Results: </strong>Among 19,539 eligible patients at day 91, inverse probability weighting created a weighted pseudopopulation of 19,758 patients (8641 HDF; 11,117 hemodialysis). During a median follow-up of 16 months (interquartile range, 6-32), 4282 deaths occurred. HDF was associated with a lower risk of all-cause mortality compared with high-flux hemodialysis (hazard ratio, 0.72; 95% confidence interval, 0.67 to 0.77). At 2 years, the weighted cumulative incidence of death was 20.6% in the HDF group and 22.3% in the hemodialysis group, corresponding to an absolute risk reduction of 1.7% points. The results were consistent across sensitivity analyses, including analyses accounting for country, competing risks, informative censoring, protocol adherence, and an intention-to-treat-like exposure definition. The association was broadly similar across prespecified subgroups, with only a stronger relative benefit observed among patients with preexisting cardiovascular disease (interaction P < 0.001). Higher delivered convective volumes were associated with better survival; however, these findings should be interpreted cautiously because higher convective volumes may reflect patient stability and center expertise rather than a causal dose-response relationship.</p><p><strong>Conclusions: </strong>In this large multinational target trial emulation, sustained high-volume postdilution HDF was associated with lower mortality than high-flux hemodialysis.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148760982","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":"Nonhistone Post-translational Modifications as Integrative Signaling Networks in Podocyte Injury and Glomerular Disease.","authors":"Zhuoying He, Hanzhi Jiang, Shaoguo Tao, Yannic Becker, Patricia Schroder, Jie Xiao, Hermann Haller, Guibao Ke","doi":"10.1681/ASN.0000001242","DOIUrl":"10.1681/ASN.0000001242","url":null,"abstract":"<p><p>Podocytes are key structural components of the glomerular filtration barrier and are essential for maintaining selective protein filtration. Podocyte dysfunction is closely associated with proteinuria and the progression of glomerulosclerosis, constituting the common pathological basis of various CKDs such as diabetic nephropathy and FSGS. While histone post-translational modifications (PTMs) have been extensively studied in podocyte biology, recent attention has shifted toward the regulatory roles of nonhistone PTMs. By modulating protein stability, activity, localization, and interactions, these modifications participate in core biological processes such as apoptosis, cytoskeletal remodeling, inflammatory signaling, and metabolic reprogramming. Nevertheless, the strength of evidence is not uniform across PTM categories. While some mechanisms have been directly demonstrated in podocytes, others are inferred mainly from broader kidney injury models or from studies in nonpodocyte cell types. Accordingly, not all reported PTM changes should be interpreted as equally well-established causal drivers of podocyte injury. This review focuses on the molecular regulatory networks and pathophysiological significance of major nonhistone PTMs, including acetylation, phosphorylation, methylation, lactylation, ubiquitination, and SUMOylation. We further propose a hypothesis-generating and integrative conceptual model of podocyte deterioration, linking initiating pathological stimuli to stress transduction and downstream effector decompensation that may culminate in structural collapse. Importantly, this proposed cascade is not intended to represent a universally validated linear sequence or a definitive disease mechanism. Rather, it provides an organizing framework to generate testable hypotheses. We further highlight the therapeutic promise of targeting nonhistone PTM pathways while acknowledging the considerable translational challenges that remain. By synthesizing the mechanistic landscape of nonhistone PTMs, this review provides an integrated framework for advancing our understanding of podocytopathy pathogenesis and fostering the development of precision-targeted therapies.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148712947","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":"Fibroblast Cyclooxygenase 2 Expression in the Development of Progressive Kidney Fibrosis.","authors":"Ming-Tsun Tsai, Mengdi Jiang, Yu Pan, Shirong Cao, Yinqiu Wang, Jianchun Chen, Shensen Li, Xinyu Dong, Wentian Luo, Agnes B Fogo, Roy Zent, Matthew H Wilson, Juan Pablo Arroyo Ornelas, Andrew S Terker, Ming-Zhi Zhang, Raymond C Harris","doi":"10.1681/ASN.0000001218","DOIUrl":"10.1681/ASN.0000001218","url":null,"abstract":"<p><strong>Key points: </strong>Cyclooxygenase 2 expression increased in kidney fibroblasts in response to a fibrotic stimulus. Fibroblast cyclooxygenase 2-mediated PGE2 promoted an anti-inflammatory, proreparative phenotype in macrophages by activating the PGE2 receptor EP4. Selective deletion of fibroblast cyclooxygenase 2 promoted a proinflammatory macrophage phenotype, which exacerbated kidney fibrosis.</p><p><strong>Background: </strong>During progressive kidney injury, pericytes and resident fibroblasts migrate, proliferate, and differentiate into myofibroblasts, which are the major source of extracellular matrix deposition. Both interstitial fibroblasts and macrophages contribute to kidney fibrosis and coexist within the fibrotic niche. However, the potential interaction between fibroblasts and macrophages and its role in kidney fibrosis remains incompletely understood. Previous studies have indicated a role for kidney prostaglandins to limit fibroblast activity and myofibroblast transformation.</p><p><strong>Methods: </strong>Inducible PDGFR β -Cre mice were crossed to the indicated floxed mice to selectively delete either cyclooxygenase 2 (COX-2) or the PGE2 receptors EP2 and EP4. Unilateral ureteral obstruction was used as a model of progressive kidney fibrosis.</p><p><strong>Results: </strong>Selective deletion of cyclooxygenase-2 expression in fibroblasts (FibCOX-2-/-) increased kidney fibrosis in association with kidney macrophages with a proinflammatory and profibrotic phenotype. The highest differentially expressed gene in these macrophages was the profibrotic factor SPP1/osteopontin, and deletion of kidney macrophages with clodronate inhibited kidney expression of SPP1 and ameliorated fibrosis in FibCOX2-/- mice.</p><p><strong>Conclusions: </strong>Our findings suggest that fibroblast COX-2 protects against progressive kidney fibrosis, potentially through a regulatory interplay that modulates the surrounding macrophage phenotype during chronic kidney injury.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684966","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":"A Vagal-Renal-Splenic Reflex Suppresses Renal Sympathetic Nerve Activity and Preserves Kidney Function after Ischemic Injury.","authors":"Mazher Mohammed, Ubong Ekperikpe, Sujit S Nair, Eric Lazartigues, Ashutosh K Tewari, Babu J Padanilam","doi":"10.1681/ASN.0000001196","DOIUrl":"10.1681/ASN.0000001196","url":null,"abstract":"<p><strong>Key points: </strong>Afferent vagus nerve stimulation (aVNS) suppressed maladaptive renal sympathetic nerve activity after ischemic injury by engaging kidney-associated vagal-autonomic circuits identified by transsynaptic tracing. Full renoprotection by aVNS required an intact spleen, revealing an integrated vagal-renal-splenic neuroimmune reflex aVNS protected kidney function, whether delivered as preconditioning before injury or 72 hours after ischemia-reperfusion injury, defining a clinically therapeutic window.</p><p><strong>Background: </strong>AKI is associated with maladaptive increases in renal sympathetic nerve activity (RSNA) and frequently progresses to CKD. Neuromodulatory strategies that suppress sympathetic outflow may provide therapeutic benefit. We tested whether afferent vagus nerve stimulation (aVNS) mitigates ischemic AKI by modulating RSNA through central autonomic circuits and splenic neuroimmune signaling.</p><p><strong>Methods: </strong>Retrograde transsynaptic pseudorabies virus tracing was used to identify neural pathways linking the kidney to vagal sensory circuits in C57BL/6J mice. RSNA, arterial pressure, and heart rate were recorded during intermittent aVNS. Bilateral renal ischemia-reperfusion injury was used to assess therapeutic efficacy. Mechanistic studies included subdiaphragmatic vagotomy, renal denervation controls, splenectomy, ganglionic blockade, and c-Fos mapping.</p><p><strong>Results: </strong>Pseudorabies virus tracing identified polysynaptic pathways linking the kidney to nodose ganglia, dorsal root ganglia, and central autonomic nuclei, with controls supporting tracer specificity. aVNS produced frequency-dependent and sustained suppression of RSNA. In ischemia-reperfusion injury, aVNS attenuated RSNA surges, preserved GFR, reduced tubular injury markers including neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, and limited fibrosis. Protection was observed with both preconditioning and delayed treatment, including stimulation initiated up to 72 hours after injury. Ganglionic blockade abolished acute aVNS responses. Splenectomy eliminated the full RSNA-lowering and renoprotective effects of aVNS, while aVNS reduced systemic norepinephrine and altered splenic signaling.</p><p><strong>Conclusions: </strong>aVNS engages kidney-associated vagal-autonomic pathways that suppress RSNA and require splenic signaling for full renoprotection after ischemic AKI.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148679024","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":"Medicare Advantage and Access to Living Donor Kidney Transplantation among Older Patients Receiving Dialysis.","authors":"Joel T Adler, Arnold E Kuk, Kelsey M Drewry, Kevin H Nguyen, Katherine Ross-Driscoll, Adam Bingaman, Stephen O Pastan, Adam S Wilk","doi":"10.1681/ASN.0000001209","DOIUrl":"10.1681/ASN.0000001209","url":null,"abstract":"<p><strong>Key points: </strong>Medicare Advantage was associated with lower kidney transplant waitlisting among older adults initiating dialysis. After waitlisting, Medicare Advantage was associated with lower living donor kidney transplantation but not deceased donor transplantation. Findings suggest payer-related barriers may differ across transplant pathway steps and living donor processes.</p><p><strong>Background: </strong>Medicare Advantage enrollment is rising among older adults with kidney failure. Compared with traditional Medicare, the contracted provider networks and utilization management of Medicare Advantage may introduce friction in transplant evaluation and living donor coordination, potentially restricting access for vulnerable beneficiaries. We examined whether Medicare Advantage is associated with access to living donor kidney transplantation and whether associations vary by rurality, age, or county-level social vulnerability.</p><p><strong>Methods: </strong>Using the United States Renal Data System, we identified adults aged 65-80 years initiating dialysis in 2015-2021 with follow-up through March 15, 2024 ( N =284,166; analytic N =279,229 with complete covariate data). Payer was classified at day 90 after dialysis initiation for waitlisting and overall incident-cohort models and at waitlisting for postwaitlisting transplant models. Fine-Gray competing risks models estimated subdistribution hazard ratios (sHRs) for time to waitlisting (death as the competing event) and, among waitlisted patients, time to any transplantation (death and delisting as competing events) and to deceased donor kidney transplantation or living donor kidney transplantation (death, delisting, and receipt of the alternate donor type as competing events). We adjusted for demographics, dual eligibility, clinical factors, rurality, and county-level Social Vulnerability Index quartiles.</p><p><strong>Results: </strong>Forty-two percent were enrolled in Medicare Advantage. Among 279,229 patients in adjusted models, 15,664 (6%) were waitlisted. Medicare Advantage was associated with lower likelihood of waitlisting versus traditional Medicare (sHR, 0.87; 95% confidence interval [CI], 0.84 to 0.90). Among waitlisted patients, Medicare Advantage was not associated with the incidence of any kidney transplantation (sHR, 0.99; 95% CI, 0.94 to 1.03) or deceased donor kidney transplantation (sHR, 1.04; 95% CI, 0.99 to 1.10) but was associated with a lower incidence of living donor kidney transplantation (sHR, 0.85; 95% CI, 0.77 to 0.94).</p><p><strong>Conclusions: </strong>Among older adults with kidney failure initiating dialysis, Medicare Advantage was associated with lower waitlisting and lower living donor kidney transplantation after waitlisting but was not associated with deceased donor kidney transplantation or any kidney transplantation after waitlisting.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148679042","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":"Protective Effect of the Apolipoprotein L1 p.N264K Variant Against CKD among People with HIV Carrying Apolipoprotein L1 High-Risk Genotypes.","authors":"Junyu Chen, Jennie Mather, Rachel K Y Hung, Qin Hui, Cheryl Winkler, David W Haas, Karen Beeri, Yuki Bradford, Marylyn Ritchie, John Booth, Rachel Hilton, Peter Wilson, Adriana Hung, Vincent C Marconi, Frank A Post, Yan V Sun","doi":"10.1681/ASN.0000001235","DOIUrl":"10.1681/ASN.0000001235","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148669793","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 Metabolic Remodeling Characterizes Injured Niches during Post-ischemic Kidney Repair.","authors":"Rosalie G J Rietjens, Benedetta Manzato, Yuheng Liao, Wendy M P J Sol, Ahmed Mahfouz, Martin Giera, Bernard M van den Berg, Sébastien J Dumas, Gangqi Wang, Ton J Rabelink","doi":"10.1681/ASN.0000001216","DOIUrl":"10.1681/ASN.0000001216","url":null,"abstract":"<p><strong>Key points: </strong>Spatial metabolomics revealed persistent injured tissue niches after ischemic injury despite the presence of apparently healthy epithelial cells. Proximal tubule cells residing in injured niches exhibited succinate accumulation and linoleic acid depletion. Integration with spatial transcriptomics showed that injured niches were characterized by dysregulated oxidative and lipid metabolism.</p><p><strong>Background: </strong>The role of the tissue microenvironment in the transition from AKI to CKD remains poorly understood. While the persistence of failed-repair proximal tubule (FR-PT) cells is postulated to hamper kidney regeneration, the spatial metabolic architecture of injured tissue and its effect on regenerative capacity have not been fully characterized.</p><p><strong>Methods: </strong>We analyzed mouse kidneys 14 days after bilateral ischemia-reperfusion injury using a multimodal spatial omics approach. Internal standard-normalized mass spectrometry imaging was used to quantify metabolite abundances, followed by unsupervised spatial domain analysis using the BANKSY algorithm to identify tissue niches on the basis of lipidome profiles. Consecutive sections underwent high-resolution spatial transcriptomics (Stereo-seq), and we applied niche projection to integrate metabolomic and transcriptomic data, enabling comparison of proximal tubule cells in healthy versus injured niches.</p><p><strong>Results: </strong>Unsupervised spatial domain analysis revealed distinct healthy and injured niches, with injured niches exhibiting diffusely spread metabolic abnormalities extending beyond FR-PT cells. Quantitative metabolomics demonstrated that seemingly healthy proximal tubule cells residing in injured niches exhibited elevated succinic acid and depleted linoleic acid compared with cells in healthy niches. Spatial transcriptomics confirmed these metabolic defects at the transcriptional level, revealing downregulation of oxidative phosphorylation and fatty acid β -oxidation pathways in proximal tubule cells within injured microenvironments.</p><p><strong>Conclusions: </strong>Combined spatially resolved analysis of internal standard-normalized mass spectrometry imaging and spatial transcriptomics revealed distinct healthy and injured tissue niches after ischemia-reperfusion injury. Metabolic abnormalities, including defects in oxidative phosphorylation and fatty acid β -oxidation, were not restricted to FR-PT cells but extended into seemingly healthy epithelial cells embedded within injured microenvironments.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.7,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148669822","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":"Design and Reporting Quality of Noninferiority Trials in Kidney Transplantation: A Systematic Review.","authors":"Bree Shi, Jonathan M Bleasel, Tracey Ying, Steven J Chadban","doi":"10.1681/ASN.0000001041","DOIUrl":"10.1681/ASN.0000001041","url":null,"abstract":"<p><strong>Key points: </strong>Many kidney transplant noninferiority trials used unjustified or overly generous margins, risking adoption of inferior therapies. Inadequate analyses, poor missing data handling, and weak Consolidated Standards of Reporting Trials (CONSORT) adherence limit trial interpretation. Stronger noninferiority trial design and reporting are needed to improve evidence quality in kidney transplantation.</p><p><strong>Background: </strong>Noninferiority trials are essential in kidney transplantation, where established standard-of-care treatments make placebo-controlled designs infeasible, and their use is increasing. We aimed to assess the design and reporting quality of noninferiority trials in kidney transplantation, specifically assessing adherence to existing guidelines.</p><p><strong>Methods: </strong>We searched medical literature analysis and retrieval system online, Embase, and Cochrane Central Register of Controlled Trials for randomized controlled noninferiority trials in kidney transplantation published up to February 2025. Two investigators reviewed and extracted data. Study quality was assessed regarding design and reporting quality using key noninferiority design criteria and the Consolidated Standards of Reporting Trials 2012 extension, respectively.</p><p><strong>Results: </strong>We identified 43 unique trials: 36 (84%) compared a novel immunosuppressive regimen to standard of care and 26 (60%) were industry sponsored. The noninferiority margin (the worst-case loss in efficacy considered clinically acceptable) was not justified in 28 (65%) studies and poorly justified in seven (16%). Of 32 studies with a categorical primary outcome, 30 (94%) assessed absolute risk reduction rather than relative risk. Most studies had high withdrawal and dropout rates, yet 33 (77%) did not specify methods for handling missing data. Intention-to-treat analysis alone was used to determine primary efficacy in 24 (56%) studies. Twelve studies (28%) provided an incorrect conclusion, most claiming equivalence when noninferiority had not been adequately demonstrated. Both design and reporting quality have improved over time ( P = 0.02, P = 0.002, respectively). No association was evident between design or reporting quality and journal impact factor or sponsor type.</p><p><strong>Conclusions: </strong>We found major deficiencies in the design, conduct, and reporting of noninferiority trials in kidney transplantation.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":"1773-1785"},"PeriodicalIF":9.7,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13441085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147290376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}