Journal of The American Society of Nephrology最新文献

{"title":"Metabolic Dysregulation of 27-Hydroxycholesterol Sensitizes Proximal Tubular Epithelial Cells to Ferroptosis in Ischemic Acute Kidney Injury.","authors":"Yi-Lin Zhang,Xin-Yan Li,Tao-Tao Tang,Qin Yang,Bo Wang,Zuo-Lin Li,Yi Wen,Qiu-Li Wu,Lin-Li Lv,Ye Feng,Xiong-Zhong Ruan,John Ci-Jiang He,Bin Wang,Bi-Cheng Liu","doi":"10.1681/asn.0000000857","DOIUrl":"https://doi.org/10.1681/asn.0000000857","url":null,"abstract":"BACKGROUNDCell death plays a pivotal role in ischemic acute kidney injury (AKI), with metabolic dysfunction emerging as a key contributor. However, the mechanism by which how metabolism imbalance initiates renal tubular cell death is poorly understood.METHODSWe used combining single-cell spatial transcriptomics and metabolomics to characterize the function and metabolites of murine renal proximal cell subpopulations during ischemic AKI to CKD transition.RESULTSFerroptosis was identified as the predominant mode of cell death in severely injured proximal straight tubules following acute kidney injury (AKI). Further investigation revealed a critical deficiency in Cyp7b1, an enzyme responsible for metabolizing 27-hydroxycholesterol (27-HC) into 7α,27-dihydroxycholesterol, resulting in substantial 27-HC accumulation in proximal tubular cells during the early phase of ischemic AKI. Mechanistically, 27-HC acts as an endogenous ligand for estrogen receptor α (ERα), inducing downstream Hmox1 activation and thereby potentiating ferroptosis susceptibility in proximal tubular cells. Notably, adeno-associated virus (AAV)-mediated Cyp7b1 overexpression in a murine ischemia-reperfusion injury (IRI) model attenuated ferroptosis by enhancing 27-HC degradation, effectively mitigating ischemic AKI progression. These findings underscore the pivotal role of the Cyp7b1/27-HC axis in this pathological context.CONCLUSIONSOur study delineated a unique mechanism of Cyp7b1/27-HC axis in proximal tubular cell ferroptosis in early AKI.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"72 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068396","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: Interpreting Rapid eGFR Decline in the Generation 100 Study.","authors":"Stein I Hallan,Knut A Langlo,Michael G Shlipak","doi":"10.1681/asn.0000000860","DOIUrl":"https://doi.org/10.1681/asn.0000000860","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"17 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068398","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: Reconsidering Biomarker Interpretation and Clinical Applicability in High-Intensity Interval Training and Kidney Function Trials.","authors":"Stein I Hallan,Knut A Langlo,Michael G Shlipak","doi":"10.1681/asn.0000000862","DOIUrl":"https://doi.org/10.1681/asn.0000000862","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"35 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068395","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":"Interpreting Rapid eGFR Decline in the Generation 100 Study.","authors":"Sebastián Cabrera,Erico Segovia","doi":"10.1681/asn.0000000859","DOIUrl":"https://doi.org/10.1681/asn.0000000859","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"89 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068397","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":"Mycophenolate Mofetil versus Cyclophosphamide for Initial Therapy in Childhood-Onset Proliferative Lupus Nephritis: A Prospective, Multicenter, Randomized Trial.","authors":"Ying Wang,Xiaoyan Li,Shan Jian,Jing Li,Junxia Yan,Shuzhen Sun,Zhenle Yang,Weimin Zheng,Qun Li,Qi Zheng,Meiping Lu,Mo Wang,Qin Yang,Huawei Mao,Tongxin Han,Yi Lin,Qiuye Zhang,Yue Du,Ying Tang,Yong Cai,Liangzhong Sun,Jianjiang Zhang,Junmei Liu,Zanhua Rong,Lijun Jiang,Haitao Bai,Yan Chen,Jun Yang,Linlin Wang,Wei Zhang,Xinyi Wei,Yun Zhu,Xiaozhong Li,Xingyuan Xie,Dujuan Zhou,Yongzhen Li,Yan Cao,Tian Shen,Qian Liu,Hongmei Song,Xiaochuan Wu, ","doi":"10.1681/asn.0000000866","DOIUrl":"https://doi.org/10.1681/asn.0000000866","url":null,"abstract":"BACKGROUNDRecent studies suggest that oral mycophenolate mofetil (MMF) may be similar to intravenous cyclophosphamide in treating lupus nephritis. However, these therapies have not been prospectively compared in childhood-onset lupus nephritis.METHODSIn this prospective, multicenter, randomized trial, patients aged 5-17 years with proliferative lupus nephritis (class III/IV ± V) and severely increased proteinuria (urine protein-creatinine ratio ≥ 1000 mg/g and/or 24-hour urinary protein excretion > 25 mg/kg) were randomly assigned to receive either MMF or intravenous cyclophosphamide as initial therapy, alongside glucocorticoids. The primary end point was total renal response at 24 weeks, with the aim of demonstrating the noninferiority of MMF compared with intravenous cyclophosphamide, using a noninferiority-margin of 12%. Total renal response encompasses complete renal response, primary efficacy renal response, and partial renal response. Secondary end points assessed systemic disease activity and safety.RESULTSA total of 107 patients were enrolled from 17 hospitals, with 52 assigned to the MMF group (47 completed the 24-week therapy) and 55 assigned to the cyclophosphamide group (48 completed the 24-week therapy). In the intention-to-treat population, the total renal response rate was 92% in the MMF group and 89% in the cyclophosphamide group (test for noninferiority, P = 0.008). In the per-protocol population, renal response was observed in 96% of patients in the MMF group versus 94% of patients in the cyclophosphamide group (test for noninferiority, P = 0.009). The difference in total renal response rate between the MMF and cyclophosphamide groups was 3% (95% CI, -9% to 15%) in the intention-to-treat population and 2% (95% CI, -9% to 13%) in the per-protocol population. There were no significant differences in the incidence of adverse drug reactions between the MMF and cyclophosphamide groups in the intention-to-treat population (10% versus 15%, continuity-correction χ2 test, P = 0.44).CONCLUSIONSAfter 24 weeks of therapy, oral mycophenolate mofetil was noninferior to intravenous cyclophosphamide as initial therapy for childhood-onset proliferative lupus nephritis and exhibited a similar safety profile.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"64 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043642","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":"Loop Diuretic Dose Intensification versus Adjuvant Thiazide for Diuretic Resistance in Acute Heart Failure: Mechanistic Randomized Controlled Trial.","authors":"Veena S Rao,Zachary L Cox,Juan B Ivey-Miranda,Julieta Moreno-Villagomez,Daniela Ramos-Mastache,Christopher Maulion,Lavanya Bellumkonda,Jeffrey Turner,F Perry Wilson,Michael G Shilpak,Michelle M Estrella,Paul Welling,Christopher S Wilcox,David H Ellison,Biff Forbush,Jeffrey M Testani","doi":"10.1681/asn.0000000887","DOIUrl":"https://doi.org/10.1681/asn.0000000887","url":null,"abstract":"BACKGROUNDThe optimal therapy for loop diuretic resistance may differ if caused by resistance at the site of action in the loop of Henle (DR-Loop) vs. compensatory distal reabsorption (DR-Distal). The study primarily aimed to compare diuretic strategies and explore if targeting the underlying diuretic resistance mechanism could optimize diuretic response.METHODSPatients hospitalized with heart failure and diuretic resistance (6-hour cumulative natriuresis <100 mmol after IV loop diuretic) were randomized 1:1 to 1) 2.5X IV loop dose intensification or 2) IV chlorothiazide addition to the same loop diuretic. The primary trial outcome was the increase in 6-hour natriuresis between strategies. Exploratory analyses of diuretic resistance mechanism were performed. Diuretic resistance mechanisms were categorized using the fractional excretion of lithium (FELi), a metric evaluating sodium exit from the loop of Henle. DR-Loop was defined as a loop diuretic induced increase in FELi below the median and DR-Distal as an increase in FELi above the median at the screening visit.RESULTSPatients (mean age 68 ±12 years, 40% women) were randomized to loop dose intensification (N=51) or adjuvant thiazide (N=52). The primary outcome of increase in 6-hour natriuresis improved significantly with both strategies. However, chlorothiazide addition produced a significantly larger improvement in 6-hour natriuresis [107 mmol increase (95% CI 81, 132)] compared to loop augmentation [49 mmol increase (95% CI 31, 66)] (treatment effect 58 mmol [95% CI 27, 89]; P<0.001). Paradoxically, loop intensification augmented natriuresis less in patients with DR-Loop compared to DR-Distal (27±39 mmol vs 75±77 mmol, respectively, P=0.004), and adjuvant thiazide did not increase natriuresis more in patients with DR-Distal versus DR-Loop (92±71 mmol vs 105±86 mmol, respectively, P=0.54).CONCLUSIONSStrategies of loop dose intensification and adjuvant thiazide both improved diuretic response, with a significantly larger augmentation of natriuresis with adjuvant thiazide. The underlying diuretic resistance mechanism did not identify a preferential response to either therapy.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"47 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043640","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":"Treatment Approaches for Alport Syndrome.","authors":"Michelle N Rheault","doi":"10.1681/ASN.0000000897","DOIUrl":"https://doi.org/10.1681/ASN.0000000897","url":null,"abstract":"<p><strong>Abstract: </strong>Alport syndrome is a progressive, hereditary disorder of basement membranes caused by variants in genes encoding the α3, α4, or α5 chains of type IV collagen (COL4A3, COL4A4, and COL4A5) leading to glomerulopathy, kidney failure, hearing loss, and eye abnormalities. Absence or dysfunction of the α3-α4-α5(IV) heterotrimer triggers multiple compensatory and detrimental pathways within all layers of the glomerular filtration barrier. Developing a therapeutic strategy for patients with Alport syndrome depends on understanding these mechanisms of disease progression that are predominant at different times throughout the disease course. These strategies may include reconstitution of the α3-α4-α5(IV) network in the GBM, reducing biomechanical strain and glomerular hyperfiltration, chaperone therapy, blocking aberrant signaling between the GBM and podocytes, reducing endothelial cell injury, reducing inflammation, and blocking fibrosis pathways.</p>","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145054103","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":"Effect of Finerenone on Morbidity and Mortality in CKD.","authors":"John W Ostrominski,Gerasimos Filippatos,Brian L Claggett,Zi Michael Miao,Akshay S Desai,Pardeep S Jhund,Alasdair Henderson,Katja Rohwedder,Meike D Brinker,Andrea Scalise,Patrick Schloemer,Carolyn S P Lam,Michele Senni,Sanjiv J Shah,Adriaan A Voors,Faiez Zannad,Peter Rossing,Luis M Ruilope,Stefan D Anker,Bertram Pitt,Rajiv Agarwal,John J V McMurray,Scott D Solomon,Muthiah Vaduganathan","doi":"10.1681/asn.0000000823","DOIUrl":"https://doi.org/10.1681/asn.0000000823","url":null,"abstract":"BACKGROUNDFinerenone has been shown to reduce cardiovascular and kidney events in individuals with chronic kidney disease (CKD) and type 2 diabetes. Pooling data from all completed outcomes trials evaluating finerenone to date may enhance understanding of its effects on morbidity and mortality in this high-risk population.METHODSIn this prespecified participant-level pooled analysis of the FIDELIO-DKD, FIGARO-DKD, and FINEARTS-HF trials (FINE-HEART), FINEARTS-HF trial participants with type 2 diabetes, CKD, and albuminuria were pooled with the persons enrolled in FIDELIO-DKD and FIGARO-DKD. Treatment effects of finerenone versus placebo on cardiovascular events, composite kidney outcomes, all-cause hospitalization, and mortality were evaluated using Cox proportional hazards regression models, stratified by trial and geographic region.RESULTSAmong 18,991 pooled trial participants, 14,180 (mean age, 65±10 years; 31% female; mean eGFR, 58±22 mL/min/1.73 m2; median UACR, 478 [IQR, 167-1103] mg/g) were included in the analysis. Finerenone reduced cardiovascular death or heart failure hospitalization (hazard ratio, 0.83; 95% CI, 0.75-0.93; P=0.001) compared with placebo, without evidence of heterogeneity according to baseline eGFR (Pinteraction=0.18), UACR (Pinteraction=0.60), or HbA1c (Pinteraction=0.51). Finerenone additionally appeared to reduce cardiovascular death, heart failure hospitalization, major adverse cardiovascular events, new-onset atrial fibrillation, and the composite kidney outcome. Benefits on the composite kidney outcome appeared greater with higher baseline UACR (Pinteraction=0.04). In sensitivity analyses evaluating a broader range of participants with CKD, finerenone appeared to consistently reduce cardiovascular death or heart failure hospitalization irrespective of 1) UACR (Pinteraction=0.22) when FINEARTS-HF participants with type 2 diabetes and at least moderate-risk CKD were included; and 2) HbA1c (Pinteraction=0.59) when FINEARTS-HF participants with albuminuric CKD but without diabetes were included. Serious adverse events were less common with finerenone versus placebo (34% vs. 36%), but hyperkalemia-related permanent treatment discontinuations were more common (2% vs. 1%).CONCLUSIONSIn this prespecified FINE-HEART analysis, finerenone reduced cardiovascular, kidney, and mortality events across a wide spectrum of CKD in persons with type 2 diabetes.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"34 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043707","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":"Kidney Disease as a Driver of Immunosenescence: Mechanisms and Potential Interventions.","authors":"Zhuolun Song,Sarah Tsou,Friederike Martin,Mukhammad Kayumov,Yao Xiao,Hao Zhou,Reza Abdi,Stefan G Tullius","doi":"10.1681/asn.0000000896","DOIUrl":"https://doi.org/10.1681/asn.0000000896","url":null,"abstract":"Immunosenescence, a state marked by immune dysfunction, chronic low-grade inflammation, and impaired pathogen defense, is accelerated in chronic kidney disease (CKD). CKD promotes systemic inflammation through the accumulation of uremic toxins, oxidative stress, and dysregulated immune signaling, all driving premature aging of both innate and adaptive immune cells. These mechanisms result in dysregulated immune activation and impaired surveillance, thereby aggravating kidney damage and increasing the risk for co-morbidities. Despite removing uremic toxins, dialysis may further accelerate immunosenescence by exposing immune cells to oxidative and antigenic stress, inducing telomere shortening and T cell exhaustion. Kidney transplantation can partially reverse CKD-induced immunosenescence by restoring renal function. Commonly used immunosuppressive agents, however, may further promote immunosenescence by impairing thymic function, depleting naïve T cells, and suppressing NK cell activity. However, mTOR inhibitors have shown anti-aging effects by promoting autophagy and inhibiting pro-inflammatory pathways. Therapeutic strategies targeting immunosenescence in CKD have been gaining momentum. Senotherapeutics can eliminate senescent cells and reduce SASP-mediated inflammation. SGLT2 inhibitors, caloric restriction, microbiome modulation, mesenchymal stem cell therapies and renal replacement therapies also offer the potential to slow accelerated immunosenescence as a consequence of CKD. Here, we provide a comprehensive overview of the mechanisms linking CKD and immunosenescence, along with emerging therapeutic strategies that have the potential to target premature aging.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"77 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043641","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":"50 Shades of Risk: Population Studies and the Genetic Architecture of Kidney Diseases.","authors":"Omid Sadeghi-Alavijeh,Melanie M Y Chan,Horia Stanescu,Daniel P Gale,Detlef Bockenhauer","doi":"10.1681/asn.0000000893","DOIUrl":"https://doi.org/10.1681/asn.0000000893","url":null,"abstract":"Genetics is transforming medicine, providing the possibility of highly specific diagnoses, which in turn allow molecularly defined cohort studies that facilitate detailed insights into gene- or even variant specific prognosis and treatments. Yet, our understanding of genetic variation is changing. Previously, genetic testing typically resulted in a binary result, where an underlying genetic cause was either identified or not. With the increasing availability of population genomic data, a more nuanced view is emerging. Many disease-associated variants can also be identified in the unaffected population and the degree of enrichment in affected persons informs on the variant-associated risk. Whereas some variants have virtually complete penetrance, conforming to the old binary paradigm, others are just mildly enriched and thus may explain only part of the aetiology. Moreover, the traditional paradigm of rare variants causing rare diseases, while common variants affect common disorders is changing, as we recognise that rare variants constitute most of the overall genetic variation and thus contribute a much higher proportion of the heritability of common disorders than previously thought. Conversely, examples are emerging of common variants that contribute to rare recessive disorders. These insights from population genetics not only inform variant interpretation, but also affect genetic counselling, especially if testing was done in a clinically unaffected individual, for instance in the context of cascade screening in the family of an affected relative. Depending on the variant-specific associated disease risk, a genetic testing result may not allow a clear distinction between affected and unaffected but only a prediction of the risk for developing the associated disease.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"73 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035798","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}