{"title":"Designing Pragmatic Trials to Better Inform Nephrology Practice.","authors":"Laura M Dember","doi":"10.1681/asn.0000001029","DOIUrl":"https://doi.org/10.1681/asn.0000001029","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"60 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005075","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}
BACKGROUNDChronic kidney disease (CKD) is a global public health challenge, yet underdiagnosis in routine care remains pervasive, leading to missed opportunities for early intervention. Evidence directly linking missed diagnosis to adverse outcomes in large, nationwide populations is limited.METHODSWe conducted a nationwide, population-based cohort study including 640,217 adults meeting KDIGO laboratory criteria for CKD (eGFR < 60 mL/min/1.73 m2 and/or UACR > 30 mg/g on at least two occasions ≥ 3 months apart) between 2000-2023. CKD underdiagnosis was defined as absence of a documented diagnosis in electronic medical records. The primary endpoint was a composite of all-cause mortality or kidney replacement therapy (KRT). Secondary endpoints included first-year mortality and time to all-cause mortality, KRT, and major cardiovascular events. Associations were assessed using multivariable Cox proportional hazards models, stratified by diabetes status, with additional propensity score-matched sensitivity analyses.RESULTSOf 640,217 patients who met laboratory criteria for CKD, 359,805 (56%) lacked a documented diagnosis. Undiagnosed patients were younger, more often female, and disproportionately from minoritized populations. Absence of a CKD diagnosis was associated with a markedly shorter time to death or KRT (hazard ratio 1.10; 95% CI, 1.09-1.11). First-year mortality was higher in undiagnosed versus diagnosed CKD (8.0% [95% CI, 7.9-8.1] vs. 4.1% [95% CI, 4.0-4.2]), despite less advanced disease at baseline.Use of reno and cardioprotective medications was significantly lower in undiagnosed patients. SGLT2 inhibitor therapy was independently associated with lower risks of death, kidney failure, and cardiovascular events, showing a consistent protective effect in both diabetic and non-diabetic subgroups. Findings were consistent across sensitivity analyses.CONCLUSIONSIn this real-world nationwide CKD cohort, underdiagnosis was common and associated with premature death, kidney failure, and cardiovascular morbidity. There was consistent association of SGLT2 inhibitors with better cardiovascular and kidney health outcomes.
{"title":"Clinical Implications of Missed CKD Diagnosis in Adults with and without Diabetes Mellitus.","authors":"Nomy Levin-Iaina,Anat Reiner-Benaim,Shaden Abu-Akel,Nayaf Habashi","doi":"10.1681/asn.0000001005","DOIUrl":"https://doi.org/10.1681/asn.0000001005","url":null,"abstract":"BACKGROUNDChronic kidney disease (CKD) is a global public health challenge, yet underdiagnosis in routine care remains pervasive, leading to missed opportunities for early intervention. Evidence directly linking missed diagnosis to adverse outcomes in large, nationwide populations is limited.METHODSWe conducted a nationwide, population-based cohort study including 640,217 adults meeting KDIGO laboratory criteria for CKD (eGFR < 60 mL/min/1.73 m2 and/or UACR > 30 mg/g on at least two occasions ≥ 3 months apart) between 2000-2023. CKD underdiagnosis was defined as absence of a documented diagnosis in electronic medical records. The primary endpoint was a composite of all-cause mortality or kidney replacement therapy (KRT). Secondary endpoints included first-year mortality and time to all-cause mortality, KRT, and major cardiovascular events. Associations were assessed using multivariable Cox proportional hazards models, stratified by diabetes status, with additional propensity score-matched sensitivity analyses.RESULTSOf 640,217 patients who met laboratory criteria for CKD, 359,805 (56%) lacked a documented diagnosis. Undiagnosed patients were younger, more often female, and disproportionately from minoritized populations. Absence of a CKD diagnosis was associated with a markedly shorter time to death or KRT (hazard ratio 1.10; 95% CI, 1.09-1.11). First-year mortality was higher in undiagnosed versus diagnosed CKD (8.0% [95% CI, 7.9-8.1] vs. 4.1% [95% CI, 4.0-4.2]), despite less advanced disease at baseline.Use of reno and cardioprotective medications was significantly lower in undiagnosed patients. SGLT2 inhibitor therapy was independently associated with lower risks of death, kidney failure, and cardiovascular events, showing a consistent protective effect in both diabetic and non-diabetic subgroups. Findings were consistent across sensitivity analyses.CONCLUSIONSIn this real-world nationwide CKD cohort, underdiagnosis was common and associated with premature death, kidney failure, and cardiovascular morbidity. There was consistent association of SGLT2 inhibitors with better cardiovascular and kidney health outcomes.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"49 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005076","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}
Sydney E Hartsell,Guo Wei,Ravinder Singh,Michael Throolin,McKenna R Nevers,Amara Sarwal,Catherine G Derington,Christa Curtis,Robert E Boucher,Jincheng Shen,Stavros Drakos,Tom Greene,Srinivasan Beddhu
BACKGROUNDHead-to-head comparisons of non-exendin glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) on kidney failure or cardiovascular-kidney-metabolic (CKM) composite endpoints are lacking. Whether kidney failure risk modifies the comparative effectiveness of GLP-1 RA versus SGLT2i is clinically relevant.METHODSWe defined a national veterans cohort with type 2 diabetes who initiated an SGLT2i, non-exendin GLP-1 RA or insulin glargine between 1/1/2018 and 12/31/2021. After applying inverse probability of treatment weighting to balance baseline characteristics, outcomes were compared across new-user groups through 3/31/2023. Outcomes included kidney failure (stage 5 chronic kidney disease or long-term renal replacement therapy), major adverse cardiac events (MACE: heart failure, myocardial infarction or stroke), CKM composite (kidney failure or MACE), all-cause death and composites of outcomes with death. We tested for effect modification by the Kidney Failure Risk Equation (KFRE) score on comparative pairwise drug effectiveness.RESULTSOut of 160,428 veterans, 53%, 14% and 34% were new-users of SGLT2i, GLP-1 RA and insulin glargine, respectively. Relative to GLP-1 RA new-users, SGLT2i new-users had similar mortality risk, a trend toward lower kidney failure risk (HR 0.89, 95% CI 0.74-1.06), but higher risk of MACE (HR 1.14, 95% CI 1.09-1.20) and CKM composite (HR 1.13, 95% CI 1.08-1.19). The effect of SGLT2i versus GLP-1 RA differed significantly between moderate-risk (2 to 6%) and high-risk (≥6%) KFRE subgroups for all outcomes except all-cause death. In those with moderate-risk KFRE, GLP-1 RA appeared more protective for kidney failure, MACE, and CKM composite, while SGLT2i appeared more protective in those with high-risk KFRE.CONCLUSIONSCompared to GLP-1 RA, SGLT2i had comparable risks of mortality, perhaps a lower risk of kidney failure, but modestly higher risk of cardiovascular events in the entire cohort. However, GLP-1 RA were more beneficial in those with moderate kidney failure risk and SGLT2i more beneficial in those with high kidney failure risk.
背景：目前缺乏对非延伸素胰高血糖素样肽-1受体激动剂（GLP-1 RA）和钠-葡萄糖共转运蛋白-2抑制剂（SGLT2i）在肾衰竭或心血管-肾代谢（CKM）复合终点的正面比较。肾衰竭风险是否改变GLP-1 RA与SGLT2i的比较有效性具有临床相关性。方法：我们定义了一组在2018年1月1日至2021年12月31日期间开始使用SGLT2i、非扩展GLP-1 RA或甘精胰岛素的2型糖尿病国家退伍军人队列。在应用治疗加权逆概率来平衡基线特征后，将新用户组的结果进行比较，直至2023年3月31日。结局包括肾衰竭（5期慢性肾脏疾病或长期肾脏替代治疗）、主要心脏不良事件（MACE：心力衰竭、心肌梗死或中风）、CKM复合（肾衰竭或MACE）、全因死亡和死亡结局复合。我们通过肾衰竭风险方程（KFRE）评分对比较两两药物有效性进行了效果修改测试。结果在160,428名退伍军人中，SGLT2i、GLP-1 RA和甘精胰岛素新使用者分别占53%、14%和34%。与GLP-1 RA新使用者相比，SGLT2i新使用者的死亡风险相似，肾功能衰竭风险较低（HR 0.89, 95% CI 0.74-1.06），但MACE （HR 1.14, 95% CI 1.09-1.20）和CKM复合（HR 1.13, 95% CI 1.08-1.19）的风险较高。除全因死亡外，SGLT2i对GLP-1 RA的影响在中度风险（2 - 6%）和高风险（≥6%）KFRE亚组之间存在显著差异。在中度风险KFRE患者中，GLP-1 RA对肾衰竭、MACE和CKM复合物具有更强的保护作用，而SGLT2i对高危KFRE患者具有更强的保护作用。结论：与GLP-1 RA相比，SGLT2i具有相当的死亡率风险，可能肾衰竭风险较低，但整个队列中心血管事件的风险较高。然而，GLP-1 RA对中度肾衰竭风险的患者更有益，而SGLT2i对高肾衰竭风险的患者更有益。
{"title":"Comparative Effectiveness of SGLT2i and GLP-1 RA on Kidney and Cardiovascular Outcomes by Kidney Failure Risk.","authors":"Sydney E Hartsell,Guo Wei,Ravinder Singh,Michael Throolin,McKenna R Nevers,Amara Sarwal,Catherine G Derington,Christa Curtis,Robert E Boucher,Jincheng Shen,Stavros Drakos,Tom Greene,Srinivasan Beddhu","doi":"10.1681/asn.0000001016","DOIUrl":"https://doi.org/10.1681/asn.0000001016","url":null,"abstract":"BACKGROUNDHead-to-head comparisons of non-exendin glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) on kidney failure or cardiovascular-kidney-metabolic (CKM) composite endpoints are lacking. Whether kidney failure risk modifies the comparative effectiveness of GLP-1 RA versus SGLT2i is clinically relevant.METHODSWe defined a national veterans cohort with type 2 diabetes who initiated an SGLT2i, non-exendin GLP-1 RA or insulin glargine between 1/1/2018 and 12/31/2021. After applying inverse probability of treatment weighting to balance baseline characteristics, outcomes were compared across new-user groups through 3/31/2023. Outcomes included kidney failure (stage 5 chronic kidney disease or long-term renal replacement therapy), major adverse cardiac events (MACE: heart failure, myocardial infarction or stroke), CKM composite (kidney failure or MACE), all-cause death and composites of outcomes with death. We tested for effect modification by the Kidney Failure Risk Equation (KFRE) score on comparative pairwise drug effectiveness.RESULTSOut of 160,428 veterans, 53%, 14% and 34% were new-users of SGLT2i, GLP-1 RA and insulin glargine, respectively. Relative to GLP-1 RA new-users, SGLT2i new-users had similar mortality risk, a trend toward lower kidney failure risk (HR 0.89, 95% CI 0.74-1.06), but higher risk of MACE (HR 1.14, 95% CI 1.09-1.20) and CKM composite (HR 1.13, 95% CI 1.08-1.19). The effect of SGLT2i versus GLP-1 RA differed significantly between moderate-risk (2 to 6%) and high-risk (≥6%) KFRE subgroups for all outcomes except all-cause death. In those with moderate-risk KFRE, GLP-1 RA appeared more protective for kidney failure, MACE, and CKM composite, while SGLT2i appeared more protective in those with high-risk KFRE.CONCLUSIONSCompared to GLP-1 RA, SGLT2i had comparable risks of mortality, perhaps a lower risk of kidney failure, but modestly higher risk of cardiovascular events in the entire cohort. However, GLP-1 RA were more beneficial in those with moderate kidney failure risk and SGLT2i more beneficial in those with high kidney failure risk.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"6 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005077","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}
The tissue microenvironment plays a pivotal role in polycystic kidney disease (PKD) progression, orchestrating cyst initiation and expansion through dynamic interactions among kidney epithelial, stromal, and immune cells, alongside systemic factors. Accurately reconstructing this complex in vivo milieu is essential to elucidate the mechanisms of PKD pathogenesis and to develop effective therapeutics. Human pluripotent stem cell-derived kidney organoids and patient-specific tubuloids have emerged as powerful platforms for modeling PKD within defined genetic contexts, faithfully recapitulating key pathological features of tubular cystogenesis. However, current organoid culture systems remain limited in their ability to replicate the full complexities of the native disease niche. Integrating bioengineering with developmental and biological insights will be essential to recreating physiologically relevant microenvironments. Such innovations will enhance the fidelity, predictive power, and translational utility of PKD organoid models, ultimately enabling more accurate drug testing and personalized therapeutics.
{"title":"Toward Physiologically Relevant Organoid Models of PKD through Microenvironment Reconstruction.","authors":"Meng Liu,Tian Zhang,Wanli Cao,Tina J Tan,Daxiang Ying,Huamin Wang,Yun Xia","doi":"10.1681/asn.0000001025","DOIUrl":"https://doi.org/10.1681/asn.0000001025","url":null,"abstract":"The tissue microenvironment plays a pivotal role in polycystic kidney disease (PKD) progression, orchestrating cyst initiation and expansion through dynamic interactions among kidney epithelial, stromal, and immune cells, alongside systemic factors. Accurately reconstructing this complex in vivo milieu is essential to elucidate the mechanisms of PKD pathogenesis and to develop effective therapeutics. Human pluripotent stem cell-derived kidney organoids and patient-specific tubuloids have emerged as powerful platforms for modeling PKD within defined genetic contexts, faithfully recapitulating key pathological features of tubular cystogenesis. However, current organoid culture systems remain limited in their ability to replicate the full complexities of the native disease niche. Integrating bioengineering with developmental and biological insights will be essential to recreating physiologically relevant microenvironments. Such innovations will enhance the fidelity, predictive power, and translational utility of PKD organoid models, ultimately enabling more accurate drug testing and personalized therapeutics.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"163 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005081","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":"Unrecognized Biases and Validation Gaps in TraceOrg for Automated Autosomal Dominant Polycystic Kidney Disease Volumetry.","authors":"Kai-Lun Sheu,Chin-Feng Tsai","doi":"10.1681/asn.0000000997","DOIUrl":"https://doi.org/10.1681/asn.0000000997","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"21 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005079","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}
Martin R Prince,Jon D Blumenfeld,Mert R Sabuncu,Anna Caroli
{"title":"Author's Reply: Unrecognized Biases and Validation Gaps in TraceOrg for Automated Autosomal Dominant Polycystic Kidney Disease Volumetry.","authors":"Martin R Prince,Jon D Blumenfeld,Mert R Sabuncu,Anna Caroli","doi":"10.1681/asn.0000000998","DOIUrl":"https://doi.org/10.1681/asn.0000000998","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"29 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005082","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}
Kidney disease represents a growing global health crisis, demanding a deeper understanding of its underlying pathophysiology. Current mechanistic efforts are often focused on discrete cell states identified by single-cell sequencing, which remains the standard for characterizing the human kidney. Crucially, these molecular atlases fail to explain how individual cell states organize and interact in specific spatial contexts to drive collective, systems-level organ failure. This Review introduces the conceptual and clinical utility of "functional communities"-spatially constrained, interacting multicellular neighborhoods -as the definitive pathological units of kidney disease. We first outline recent advances in spatial and multi-omic technologies that are essential for resolving the composition and communication networks of these communities in situ. This is followed by a deconstruction of three archetypal pathological communities: the maladaptive repair niche that is linked to chronic injury, the pro-fibrotic niche driven by specific fibroblast subtypes, and the tissue-destructive immune niche. Moreover, by integrating artificial intelligence and multi-omics data, it is possible to build virtual models capable of simulating and predicting dynamic intercellular interactions in kidney diseases. Finally, we discuss key challenges and future directions for translating this community-centric view into novel diagnostics and therapeutics. This framework offers a robust, integrated strategy for identifying vulnerable microenvironments, thereby guiding the development of next-generation diagnostics and targeted therapeutic interventions.
{"title":"Beyond the Cell Atlas: Functional Communities as the Essential Pathological Units Driving Kidney Disease.","authors":"Yiming Li,Tingkun Ma,Hao Lu,Yiping Yan,Yucheng Xue,Jinmeng Suo,Yusheng Chen,Zhiyong Peng","doi":"10.1681/asn.0000001023","DOIUrl":"https://doi.org/10.1681/asn.0000001023","url":null,"abstract":"Kidney disease represents a growing global health crisis, demanding a deeper understanding of its underlying pathophysiology. Current mechanistic efforts are often focused on discrete cell states identified by single-cell sequencing, which remains the standard for characterizing the human kidney. Crucially, these molecular atlases fail to explain how individual cell states organize and interact in specific spatial contexts to drive collective, systems-level organ failure. This Review introduces the conceptual and clinical utility of \"functional communities\"-spatially constrained, interacting multicellular neighborhoods -as the definitive pathological units of kidney disease. We first outline recent advances in spatial and multi-omic technologies that are essential for resolving the composition and communication networks of these communities in situ. This is followed by a deconstruction of three archetypal pathological communities: the maladaptive repair niche that is linked to chronic injury, the pro-fibrotic niche driven by specific fibroblast subtypes, and the tissue-destructive immune niche. Moreover, by integrating artificial intelligence and multi-omics data, it is possible to build virtual models capable of simulating and predicting dynamic intercellular interactions in kidney diseases. Finally, we discuss key challenges and future directions for translating this community-centric view into novel diagnostics and therapeutics. This framework offers a robust, integrated strategy for identifying vulnerable microenvironments, thereby guiding the development of next-generation diagnostics and targeted therapeutic interventions.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"57 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005080","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":"Artificial Intelligence for Diagnostic Pathology in Nephrology.","authors":"Jakob Nikolas Kather","doi":"10.1681/asn.0000001000","DOIUrl":"https://doi.org/10.1681/asn.0000001000","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"22 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005083","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}
Michael S Balzer,Jianfu Zhou,Amin Abedini,Ziyuan Ma,Yanjuan Hou,Tejaswini Yadav,Manuel Grundmann,Mira Pavkovic,Katalin Susztak
BACKGROUNDDiabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. Renin angiotensin-aldosterone system (RAAS) inhibitors such as enalapril have been used for decades as antiproteinuric, antihypertensive, and kidney protective agents. Still, the exact cell type of action and the molecular mechanism of drug action are elusive. Previous work has primarily emphasized injury patterns in the proximal nephron, leaving potential contributions of other nephron segments insufficiently characterized.METHODSHere, we leveraged state-of-the-art single-cell transcriptomics in the ZSF1 obese rat to elucidate potential target cells and driver molecules exerting enalapril drug effects.RESULTSWe identified injured cell states of the distal nephron in the context of prolonged enalapril treatment. We showed cathepsin D (Ctsd), a tissue RAAS effector, as an important regulator of enalapril effects and revealed Trem2+ residential macrophages as top receivers of distal nephron-derived signals. Finally, we showed that enalapril-associated gene signatures allow stratification of human kidney samples by disease-relevant outcome measures such as kidney function and fibrosis.CONCLUSIONSWe reported CTSD as an important regulator of enalapril effects, involving crosstalk between the distal nephron and TREM2+ residential macrophages. We also demonstrated that enalapril-associated gene signatures allow stratification of human kidney samples by disease-relevant outcome measures.
{"title":"Single-Cell Resolution Drug Effects of Renin-Angiotensin-Aldosterone Blockade in ZSF1 Rat Diabetic Kidney Disease.","authors":"Michael S Balzer,Jianfu Zhou,Amin Abedini,Ziyuan Ma,Yanjuan Hou,Tejaswini Yadav,Manuel Grundmann,Mira Pavkovic,Katalin Susztak","doi":"10.1681/asn.0000000995","DOIUrl":"https://doi.org/10.1681/asn.0000000995","url":null,"abstract":"BACKGROUNDDiabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. Renin angiotensin-aldosterone system (RAAS) inhibitors such as enalapril have been used for decades as antiproteinuric, antihypertensive, and kidney protective agents. Still, the exact cell type of action and the molecular mechanism of drug action are elusive. Previous work has primarily emphasized injury patterns in the proximal nephron, leaving potential contributions of other nephron segments insufficiently characterized.METHODSHere, we leveraged state-of-the-art single-cell transcriptomics in the ZSF1 obese rat to elucidate potential target cells and driver molecules exerting enalapril drug effects.RESULTSWe identified injured cell states of the distal nephron in the context of prolonged enalapril treatment. We showed cathepsin D (Ctsd), a tissue RAAS effector, as an important regulator of enalapril effects and revealed Trem2+ residential macrophages as top receivers of distal nephron-derived signals. Finally, we showed that enalapril-associated gene signatures allow stratification of human kidney samples by disease-relevant outcome measures such as kidney function and fibrosis.CONCLUSIONSWe reported CTSD as an important regulator of enalapril effects, involving crosstalk between the distal nephron and TREM2+ residential macrophages. We also demonstrated that enalapril-associated gene signatures allow stratification of human kidney samples by disease-relevant outcome measures.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"30 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005089","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: Proteomic CKD Prediction in Type 2 Diabetes: Underexplored Limitations and Translational Gaps.","authors":"Chloe Yu-Yan Cheung,Chi-Ho Lee,Karen Siu-Ling Lam,Aimin Xu","doi":"10.1681/asn.0000000992","DOIUrl":"https://doi.org/10.1681/asn.0000000992","url":null,"abstract":"","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"39 1","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005084","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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