Seminars in nephrology最新文献

{"title":"The Role of the Epidermal Growth Factor Receptor in Kidney Tubulointerstitial Fibrosis","authors":"Raymond C. Harris MD,&nbsp;Ming-zhi Zhang MD","doi":"10.1016/j.semnephrol.2026.151690","DOIUrl":"10.1016/j.semnephrol.2026.151690","url":null,"abstract":"<div><div>Kidney fibrosis is a common cause of chronic kidney disease. Experimental studies have demonstrated a role for the epidermal growth factor receptor (EGFR) signaling pathway in mediating the development and progression of kidney fibrosis. Deletion of <em>Rhbdf2</em> (iRhom2), a member of the rhomboid family that regulates A disintegrin and metalloproteinase domain 17-mediated release of membrane-anchored proteins, including EGFR ligands, inhibited kidney interstitial fibrosis, which was accompanied by decreased EGFR activation in interstitial fibroblasts/myofibroblasts. In addition, overexpression of another EGFR ligand, heparin-binding epidermal growth factor-like growth factor, induced interstitial fibrosis in kidneys. Although EGFR activation did not induce myofibroblast transformation, it was necessary for the initial pericyte/fibroblast migration and proliferation prior to subsequent myofibroblast transformation by transforming growth factor beta or other profibrotic factors. Therefore, EGFR activation in kidney fibroblasts and pericytes serves as a specific initiator of interstitial fibrosis in response to kidney injury by stimulating pericyte/fibroblast migration and proliferation. These findings may also provide insight into the development of fibrosis in other organs and in other conditions.</div></div><div>Kidney fibrosis is a common cause of chronic kidney disease. Experimental studies have demonstrated a role for the epidermal growth factor receptor (EGFR) signaling pathway in mediating the development and progression of kidney fibrosis. Deletion of <em>Rhbdf2</em> (iRhom2), a member of the rhomboid family that regulates A disintegrin and metalloproteinase domain 17-mediated release of membrane-anchored proteins, including EGFR ligands, inhibited kidney interstitial fibrosis, which was accompanied by decreased EGFR activation in interstitial fibroblasts/myofibroblasts. In addition, overexpression of another EGFR ligand, heparin-binding epidermal growth factor-like growth factor, induced interstitial fibrosis in kidneys. Although EGFR activation did not induce myofibroblast transformation, it was necessary for the initial pericyte/fibroblast migration and proliferation prior to subsequent myofibroblast transformation by transforming growth factor beta or other profibrotic factors. Therefore, EGFR activation in kidney fibroblasts and pericytes serves as a specific initiator of interstitial fibrosis in response to kidney injury by stimulating pericyte/fibroblast migration and proliferation. These findings may also provide insight into the development of fibrosis in other organs and in other conditions.</div>","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"46 2","pages":"Article 151690"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147310066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic Kidney Disease Progression Mechanisms: Why They Matter in an Era of Novel Kidney Protective Therapies","authors":"Maarten W. Taal MBChB, MMed, MD, FRCP","doi":"10.1016/j.semnephrol.2026.151692","DOIUrl":"10.1016/j.semnephrol.2026.151692","url":null,"abstract":"<div><div>Research over several decades has identified multiple factors that contribute to a complex pathway of mechanisms that drive the progression of chronic kidney disease (CKD) across all etiologies. These include glomerular hypertension and hyperfiltration, proteinuria, and tubulointerstitial fibrosis. These endeavors identified multiple therapeutic targets for achieving kidney protection, starting with angiotensin II, which led to the development of renin-angiotensin-aldosterone system inhibitors as the first effective kidney protective therapies. Following a long period of stagnation, several additional kidney protective drug classes have been developed, including sodium glucose cotransporter 2 inhibitors, nonsteroidal mineralocorticoid antagonists, and glucagon-like peptide-1 receptor agonists. The effects of all of these drugs can readily be understood within the framework of previously described CKD progression mechanisms. The development of additional novel kidney protective drug classes has been informed by our understanding of progression mechanisms and include endothelin receptor antagonists, soluble guanylate cyclase stimulators or activators, and aldosterone synthase inhibitors. This review of novel therapies in the light of CKD progression mechanisms highlights the importance of ongoing research to identify new therapeutic targets as we seek to achieve complete arrest and even reversal of CKD progression.</div></div><div>Research over several decades has identified multiple factors that contribute to a complex pathway of mechanisms that drive the progression of chronic kidney disease (CKD) across all etiologies. These include glomerular hypertension and hyperfiltration, proteinuria, and tubulointerstitial fibrosis. These endeavors identified multiple therapeutic targets for achieving kidney protection, starting with angiotensin II, which led to the development of renin-angiotensin-aldosterone system inhibitors as the first effective kidney protective therapies. Following a long period of stagnation, several additional kidney protective drug classes have been developed, including sodium glucose cotransporter 2 inhibitors, nonsteroidal mineralocorticoid antagonists, and glucagon-like peptide-1 receptor agonists. The effects of all of these drugs can readily be understood within the framework of previously described CKD progression mechanisms. The development of additional novel kidney protective drug classes has been informed by our understanding of progression mechanisms and include endothelin receptor antagonists, soluble guanylate cyclase stimulators or activators, and aldosterone synthase inhibitors. This review of novel therapies in the light of CKD progression mechanisms highlights the importance of ongoing research to identify new therapeutic targets as we seek to achieve complete arrest and even reversal of CKD progression.</div>","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"46 2","pages":"Article 151692"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147318213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Barry M. Brenner—The Exceptional Global Nephrologist Clinician, Scientist, Author, Leader—A Personal Tribute","authors":"John H. Dirks CM, FRSC, MD, FRCPC DSc","doi":"10.1016/j.semnephrol.2026.151677","DOIUrl":"10.1016/j.semnephrol.2026.151677","url":null,"abstract":"","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"46 2","pages":"Article 151677"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149175697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proposed Role for Quantitative Podocyturia as a Clinical Marker of Systemic Endothelial Injury: Implications for Cardiovascular Disease and Longevity","authors":"Kamal F. Badr MD","doi":"10.1016/j.semnephrol.2026.151685","DOIUrl":"10.1016/j.semnephrol.2026.151685","url":null,"abstract":"<div><div>Cardiovascular disease (CVD) remains the leading disability burden and cause of mortality worldwide. As emphasized by the cardiovascular-kidney-metabolic health construct, enhanced screening mechanisms are needed for the identification and prediction of subclinical endothelial injury and silent CVD. We hypothesized that urinary podocyte shedding (podocyturia), as a biomarker of ongoing glomerular endothelial injury, may be an earlier predictor of CVD than moderate albuminuria. Urinary podocin and nephrin messenger RNAs (podocyturia), as candidate biomarkers of endothelial/podocyte injury, were measured by quantitative polymerase chain reaction in type 2 diabetics with normal albumin excretion rates at baseline, at 3-4 years, and at 7 years. The development of CVD was collected as the outcome. On visit 1, podocyturia was significantly higher in individuals who subsequently developed CVD versus those who did not. We also found a significant association between podocyturia and obstructive coronary artery disease. Moreover, individuals with CVD risk factors that included male sex, metabolic syndrome, and type 2 diabetes were found to have significantly higher urinary podocin levels than individuals without these risk factors. Podocyturia may be an earlier predictor of cardiovascular events than moderate albuminuria.</div></div><div>Cardiovascular disease (CVD) remains the leading disability burden and cause of mortality worldwide. As emphasized by the cardiovascular-kidney-metabolic health construct, enhanced screening mechanisms are needed for the identification and prediction of subclinical endothelial injury and silent CVD. We hypothesized that urinary podocyte shedding (podocyturia), as a biomarker of ongoing glomerular endothelial injury, may be an earlier predictor of CVD than moderate albuminuria. Urinary podocin and nephrin messenger RNAs (podocyturia), as candidate biomarkers of endothelial/podocyte injury, were measured by quantitative polymerase chain reaction in type 2 diabetics with normal albumin excretion rates at baseline, at 3-4 years, and at 7 years. The development of CVD was collected as the outcome. On visit 1, podocyturia was significantly higher in individuals who subsequently developed CVD versus those who did not. We also found a significant association between podocyturia and obstructive coronary artery disease. Moreover, individuals with CVD risk factors that included male sex, metabolic syndrome, and type 2 diabetes were found to have significantly higher urinary podocin levels than individuals without these risk factors. Podocyturia may be an earlier predictor of cardiovascular events than moderate albuminuria.</div>","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"46 2","pages":"Article 151685"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147444902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current Options for Kidney Protection: Are Renin–Angiotensin System Inhibitors Still Relevant?","authors":"Waichi Wong MD","doi":"10.1016/j.semnephrol.2026.151689","DOIUrl":"10.1016/j.semnephrol.2026.151689","url":null,"abstract":"<div><div>Chronic kidney disease progresses through convergent mechanisms involving hemodynamic stress, proteinuria, inflammation, fibrosis, and metabolic disturbance. Barry Brenner’s hyperfiltration hypothesis established these processes as drivers of ongoing injury, and landmark trials established that renin–angiotensin–aldosterone system (RAAS) inhibition slows progression and improves clinical outcomes, marking a shift from supportive care to disease-modifying treatment. Treatment options have since expanded, with newer therapeutic classes providing additional kidney and cardiovascular benefit alongside emerging agents with more targeted mechanisms of action. Approaches to prognostic assessment have also advanced through biomarkers, genetics, imaging, and digital tools, although integration into clinical practice remains incomplete. More than 4 decades after their introduction, RAAS inhibitors remain a core component of kidney protection, with newer therapies complementing rather than replacing them.</div></div><div>Chronic kidney disease progresses through convergent mechanisms involving hemodynamic stress, proteinuria, inflammation, fibrosis, and metabolic disturbance. Barry Brenner’s hyperfiltration hypothesis established these processes as drivers of ongoing injury, and landmark trials established that renin–angiotensin–aldosterone system (RAAS) inhibition slows progression and improves clinical outcomes, marking a shift from supportive care to disease-modifying treatment. Treatment options have since expanded, with newer therapeutic classes providing additional kidney and cardiovascular benefit alongside emerging agents with more targeted mechanisms of action. Approaches to prognostic assessment have also advanced through biomarkers, genetics, imaging, and digital tools, although integration into clinical practice remains incomplete. More than 4 decades after their introduction, RAAS inhibitors remain a core component of kidney protection, with newer therapies complementing rather than replacing them.</div>","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"46 2","pages":"Article 151689"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148362387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"On the Discovery of Glomerular Capillary Hypertension: A Homage to Barry M. Brenner, MD","authors":"Richard J. Glassock MD","doi":"10.1016/j.semnephrol.2026.151678","DOIUrl":"10.1016/j.semnephrol.2026.151678","url":null,"abstract":"<div><div>Glomerular capillary hypertension plays a key role in the pathophysiologic response to kidney injury, including glomerulonephritis, diabetes mellitus, and congenital or acquired nephron loss. The discovery of this phenomenon was a transforming period in the history of nephrology. This essay describes this event and how it impacted the field, with an emphasis on the seminal contributions of Barry M. Brenner and his colleagues.</div></div><div>Glomerular capillary hypertension plays a key role in the pathophysiologic response to kidney injury, including glomerulonephritis, diabetes mellitus, and congenital or acquired nephron loss. The discovery of this phenomenon was a transforming period in the history of nephrology. This essay describes this event and how it impacted the field, with an emphasis on the seminal contributions of Barry M. Brenner and his colleagues.</div>","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"46 2","pages":"Article 151678"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149175698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond Single-Nephron Glomerular Filtration Rate: Barry Brenner, the Man I Knew","authors":"Reza Abdi MD","doi":"10.1016/j.semnephrol.2026.151680","DOIUrl":"10.1016/j.semnephrol.2026.151680","url":null,"abstract":"","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"46 2","pages":"Article 151680"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149175701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kidney Protection Options in 2025: Are Renin-Angiotensin System Inhibitors Still Needed?","authors":"Matthew R. Weir MD","doi":"10.1016/j.semnephrol.2026.151688","DOIUrl":"10.1016/j.semnephrol.2026.151688","url":null,"abstract":"<div><div>The therapeutic advantage of angiotensin-converting enzyme inhibitors was first described more than 40 years ago by Brenner and colleagues. Since then, a number of clinical trials have demonstrated the utility of drugs that modify the renin-angiotensin system (RAS) to slow the rate of progression of kidney disease in patients with and without diabetes. However, despite the well-known benefits of these drugs in reducing cardiorenal events, most clinicians are not using them consistently in their practice. The lack of use is related to concerns about increases in serum creatinine and the development of hyperkalemia. With the advent of many newer drugs to delay the progression of kidney disease and reduce the likelihood of cardiovascular events which have lesser effects on increasing serum creatinine or potassium, clinicians may prefer to use these therapies. Although trials of the newer cardiorenal protective therapies were conducted on the background of RAS inhibition, only the highest tolerated dose of RAS inhibition was used, a dose not shown to provide cardiorenal protection in a clinical trial. As multimodal therapy for slowing the progression of chronic kidney disease and reducing cardiovascular events moves into prime time, one has to wonder whether RAS inhibition will remain a foundation therapy.</div></div><div>The therapeutic advantage of angiotensin-converting enzyme inhibitors was first described more than 40 years ago by Brenner and colleagues. Since then, a number of clinical trials have demonstrated the utility of drugs that modify the renin-angiotensin system (RAS) to slow the rate of progression of kidney disease in patients with and without diabetes. However, despite the well-known benefits of these drugs in reducing cardiorenal events, most clinicians are not using them consistently in their practice. The lack of use is related to concerns about increases in serum creatinine and the development of hyperkalemia. With the advent of many newer drugs to delay the progression of kidney disease and reduce the likelihood of cardiovascular events which have lesser effects on increasing serum creatinine or potassium, clinicians may prefer to use these therapies. Although trials of the newer cardiorenal protective therapies were conducted on the background of RAS inhibition, only the highest tolerated dose of RAS inhibition was used, a dose not shown to provide cardiorenal protection in a clinical trial. As multimodal therapy for slowing the progression of chronic kidney disease and reducing cardiovascular events moves into prime time, one has to wonder whether RAS inhibition will remain a foundation therapy.</div>","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"46 2","pages":"Article 151688"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147349036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Barry Morton Brenner, MD, Memorial Publication (Gedenkschrift)","authors":"Joseph V. Bonventre MD, PhD","doi":"10.1016/j.semnephrol.2026.151725","DOIUrl":"10.1016/j.semnephrol.2026.151725","url":null,"abstract":"","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"46 2","pages":"Article 151725"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mentoring at a Distance: Atrial Peptides, the Inner Medullary Collecting Duct, Barry Brenner and Me","authors":"Mark L. Zeidel MD","doi":"10.1016/j.semnephrol.2026.151682","DOIUrl":"10.1016/j.semnephrol.2026.151682","url":null,"abstract":"<div><div>While leading groundbreaking research into glomerular function and diseases, Barry Brenner developed a world-leading division of nephrology which made important discoveries in other aspects of renal function and disease. Barry’s superb intellect, insistence on high standards and driving curiosity forged the careers of many fellows and junior faculty members who did not work on the glomerulus. As an example of this “mentorship at a distance” (along the nephron, that is) I describe here his role in developing my own line of investigation into the control of distal nephron function, starting with a series of studies on the role of atrial peptides in regulating sodium transport in inner medullary collecting duct cells. With Barry’s help and encouragement, these initial studies extended to a series of articles on the mechanisms of action of several regulators of salt excretion, work which launched my career as an independent investigator. My own story serves as a case study of the outstanding mentoring that Barry provided, even to trainees who were not focused on his own work in the glomerulus.</div></div>","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"46 2","pages":"Article 151682"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149175702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}