Seminars in nephrology最新文献

{"title":"Tension at the Barrier: Intraglomerular Pressure and the Podocyte Response","authors":"Martin R. Pollak MD","doi":"10.1016/j.semnephrol.2026.151684","DOIUrl":"10.1016/j.semnephrol.2026.151684","url":null,"abstract":"<div><div>I synthesize how systemic drivers (hypertension, diabetes, renin-angiotensin-aldosterone system activation) elevate glomerular capillary hydrostatic pressure and cyclic strain and how podocytes sense and respond to these loads via integrins, the slit diaphragm, and stretch-activated ion channels. When podocytes’ normal adaptation mechanisms are overwhelmed by higher loads, inflammatory priming, genetic risk, or loss of cytoskeletal resilience, podocytes retract, detach, and are not meaningfully replaced, driving progressive glomerulosclerosis. Therapeutically, benefit follows two complementary strategies: lowering glomerular capillary hydrostatic pressure (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, sodium-glucose cotransporter 2 inhibitors, endothelin antagonism) and reinforcing podocyte mechanoadaptation (stabilizing actin/adhesion, modulating Ca²⁺ signaling, targeting load-sensing nodes). Taken together, progressive glomerulosclerosis is best explained by a model in which elevated single-nephron pressure loads exceed podocyte mechanoadaptive capacity. Durable protection will therefore require concurrent control of intraglomerular pressure and podocyte mechanotransduction.</div></div><div>I synthesize how systemic drivers (hypertension, diabetes, renin-angiotensin-aldosterone system activation) elevate glomerular capillary hydrostatic pressure and cyclic strain and how podocytes sense and respond to these loads via integrins, the slit diaphragm, and stretch-activated ion channels. When podocytes’ normal adaptation mechanisms are overwhelmed by higher loads, inflammatory priming, genetic risk, or loss of cytoskeletal resilience, podocytes retract, detach, and are not meaningfully replaced, driving progressive glomerulosclerosis. Therapeutically, benefit follows two complementary strategies: lowering glomerular capillary hydrostatic pressure (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, sodium-glucose cotransporter 2 inhibitors, endothelin antagonism) and reinforcing podocyte mechanoadaptation (stabilizing actin/adhesion, modulating Ca²⁺ signaling, targeting load-sensing nodes). Taken together, progressive glomerulosclerosis is best explained by a model in which elevated single-nephron pressure loads exceed podocyte mechanoadaptive capacity. Durable protection will therefore require concurrent control of intraglomerular pressure and podocyte mechanotransduction.</div>","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"46 2","pages":"Article 151684"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147271892","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":"The Physician Innovator – stepping off the well-worn road to find new solutions","authors":"Jochen Reiser M.D., Ph.D.,&nbsp;Shikha Wadhwani M.D.,&nbsp;Mehmet M. Altintas Ph.D.","doi":"10.1016/j.semnephrol.2026.151683","DOIUrl":"10.1016/j.semnephrol.2026.151683","url":null,"abstract":"","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"46 2","pages":"Article 151683"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149175699","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":"Dr Barry Brenner: Respected Teacher to Many Nephrologists Around the World","authors":"Mai Rosenberg MD, ScDr(med)","doi":"10.1016/j.semnephrol.2026.151679","DOIUrl":"10.1016/j.semnephrol.2026.151679","url":null,"abstract":"","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"46 2","pages":"Article 151679"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149175700","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: Pioneering Insights That Shaped Kidney Transplantation","authors":"Anil Chandraker MD, FASN, FAST, FRCP,&nbsp;Ravinder K Wali MBBS, MD","doi":"10.1016/j.semnephrol.2026.151681","DOIUrl":"10.1016/j.semnephrol.2026.151681","url":null,"abstract":"<div><div>Barry M. Brenner (1937–2024) revolutionized nephrology by demonstrating how nephron number and glomerular hyperfiltration shape the trajectory of kidney disease. His influence reaches deeply into transplantation medicine, where his program of research established that nephron mass at the time of transplantation is a principal determinant of long-term graft outcome, that intraglomerular hypertension is a final common pathway of chronic injury, and that renin–angiotensin system (RAAS) blockade confers graft protection. These insights migrated from bench to bedside through the evaluation and long-term protection of living kidney donors, were embedded in international guidelines and national policy, and ultimately helped catalyze the development of composite biomarkers—most notably the iBox Scoring System—now advancing through regulatory qualification as a surrogate endpoint. By validating different biomarkers, such as proteinuria, estimated GFR (eGFR) slope, and histopathology as meaningful predictors of outcome, Brenner also reshaped the design of clinical trials in kidney transplantation. This review synthesizes his contributions across experimental models, living donation, biomarker science, guideline/policy translation, and clinical trials, and argues that the field’s contemporary architecture bears the imprint of Brenner’s physiologic vision.</div></div><div>Barry M. Brenner (1937–2024) revolutionized nephrology by demonstrating how nephron number and glomerular hyperfiltration shape the trajectory of kidney disease. His influence reaches deeply into transplantation medicine, where his program of research established that nephron mass at the time of transplantation is a principal determinant of long-term graft outcome, that intraglomerular hypertension is a final common pathway of chronic injury, and that renin–angiotensin system (RAAS) blockade confers graft protection. These insights migrated from bench to bedside through the evaluation and long-term protection of living kidney donors, were embedded in international guidelines and national policy, and ultimately helped catalyze the development of composite biomarkers—most notably the iBox Scoring System—now advancing through regulatory qualification as a surrogate endpoint. By validating different biomarkers, such as proteinuria, estimated GFR (eGFR) slope, and histopathology as meaningful predictors of outcome, Brenner also reshaped the design of clinical trials in kidney transplantation. This review synthesizes his contributions across experimental models, living donation, biomarker science, guideline/policy translation, and clinical trials, and argues that the field’s contemporary architecture bears the imprint of Brenner’s physiologic vision.</div>","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"46 2","pages":"Article 151681"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149175924","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":"From Nephron Number to Global Health","authors":"Valerie A. Luyckx MBBCh, MSc, PhD","doi":"10.1016/j.semnephrol.2026.151691","DOIUrl":"10.1016/j.semnephrol.2026.151691","url":null,"abstract":"&lt;div&gt;&lt;div&gt;In 1988, in a seminal paper, Brenner and colleagues proposed that the numbers of nephrons acquired in utero may be a factor that determines an individual’s lifelong risk of kidney disease. The hypothesis posited that a kidney with fewer nephrons would have a reduced filtration surface, a reduced capacity to excrete sodium, and a limited capacity to compensate for additional kidney injury and nephron loss. These factors increase the risk of high blood pressure and kidney dysfunction. Potential clinical markers for such risk include preterm birth, small-for-gestational-age birth and low birth weight, which have been associated with reduced nephron numbers and with population-level risk of kidney disease and kidney failure. As such, these birth circumstances are now recognized in mainstream guidelines on the identification of individuals at risk of kidney disease. Importantly, these circumstances depend to a large degree on maternal health in pregnancy, which, in turn, depends on many social and structural determinants of health. Optimization of maternal, fetal, and child health through achievement of the sustainable development goals therefore offers an opportunity to mitigate the growing global burden of kidney disease through supporting healthy fetal kidney development and minimizing the accumulation of additional kidney stressors throughout life. Awareness of the importance of nephron number for individual kidney health could translate into strategies to promote global kidney health.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;In 1988, in a seminal paper, Brenner and colleagues proposed that the numbers of nephrons acquired in utero may be a factor that determines an individual’s lifelong risk of kidney disease. The hypothesis posited that a kidney with fewer nephrons would have a reduced filtration surface, a reduced capacity to excrete sodium, and a limited capacity to compensate for additional kidney injury and nephron loss. These factors increase the risk of high blood pressure and kidney dysfunction. Potential clinical markers for such risk include preterm birth, small-for-gestational-age birth and low birth weight, which have been associated with reduced nephron numbers and with population-level risk of kidney disease and kidney failure. As such, these birth circumstances are now recognized in mainstream guidelines on the identification of individuals at risk of kidney disease. Importantly, these circumstances depend to a large degree on maternal health in pregnancy, which, in turn, depends on many social and structural determinants of health. Optimization of maternal, fetal, and child health through achievement of the sustainable development goals therefore offers an opportunity to mitigate the growing global burden of kidney disease through supporting healthy fetal kidney development and minimizing the accumulation of additional kidney stressors throughout life. Awareness of the importance of nephron number for individual kidney health could translate int","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"46 2","pages":"Article 151691"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147348999","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":"Glomerular Disease in Vietnam: Diagnosis and Treatment Challenges","authors":"Huong T.B. Tran,&nbsp;Thang H.D. Tran,&nbsp;David Harris","doi":"10.1016/j.semnephrol.2026.151693","DOIUrl":"10.1016/j.semnephrol.2026.151693","url":null,"abstract":"<div><div>Glomerular disease (GD) is common in Vietnam. In the absence of suitable pathology laboratories, well-trained renal pathologists and etiologic laboratory tests, the diagnosis of GD mainly relies on the recognition of clinical syndromes. Support from the International Society of Nephrology has been crucial for the clinical and pathologic diagnosis of GD in Vietnam. The high cost of new immunosuppressant agents has precluded their widespread adoption and low-cost steroids remain the main immunosuppressants prescribed for GD in Vietnam.</div></div><div>Glomerular disease (GD) is common in Vietnam. In the absence of suitable pathology laboratories, well-trained renal pathologists and etiologic laboratory tests, the diagnosis of GD mainly relies on the recognition of clinical syndromes. Support from the International Society of Nephrology has been crucial for the clinical and pathologic diagnosis of GD in Vietnam. The high cost of new immunosuppressant agents has precluded their widespread adoption and low-cost steroids remain the main immunosuppressants prescribed for GD in Vietnam.</div>","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"46 2","pages":"Article 151693"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148437884","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":"Of Diuretics, Transporters, and Mechanisms of Hypertension","authors":"Maria Castañeda-Bueno PhD,&nbsp;Gerardo Gamba MD, PhD","doi":"10.1016/j.semnephrol.2026.151686","DOIUrl":"10.1016/j.semnephrol.2026.151686","url":null,"abstract":"<div><div>As Director of the Renal Division at Brigham and Women’s Hospital, Dr Barry Brenner established a molecular physiology laboratory during the 1980s by recruiting the appropriate researchers, with the vision that cloning the complementary DNA of membrane proteins would be a critical step in advancing the field. In the early 1990s, this laboratory identified and cloned several key complementary DNAs, including those for the renal sodium-chloride and sodium-potassium-chloride cotransporter, the inwardly rectifying renal outer medullary potassium channel, and the calcium-sensing receptor. In the present work, we discuss some of the many advances regarding the physiology and pathophysiology of salt transport in the kidney that have emerged over the last 30 years, advances made possible by the cloning of these genes and, ultimately, by the vision of Barry Brenner.</div></div><div>As Director of the Renal Division at Brigham and Women’s Hospital, Dr Barry Brenner established a molecular physiology laboratory during the 1980s by recruiting the appropriate researchers, with the vision that cloning the complementary DNA of membrane proteins would be a critical step in advancing the field. In the early 1990s, this laboratory identified and cloned several key complementary DNAs, including those for the renal sodium-chloride and sodium-potassium-chloride cotransporter, the inwardly rectifying renal outer medullary potassium channel, and the calcium-sensing receptor. In the present work, we discuss some of the many advances regarding the physiology and pathophysiology of salt transport in the kidney that have emerged over the last 30 years, advances made possible by the cloning of these genes and, ultimately, by the vision of Barry Brenner.</div>","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"46 2","pages":"Article 151686"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147310030","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 Transplants From Marginal Donors: From Brenner’s Abstract to Double Kidney Transplantation in Humans","authors":"Monica Cortinovis BiotechD,&nbsp;Norberto Perico MD,&nbsp;Giuseppe Remuzzi MD, FRCP","doi":"10.1016/j.semnephrol.2026.151687","DOIUrl":"10.1016/j.semnephrol.2026.151687","url":null,"abstract":"<div><div>“In 1993, based on findings from their experimental studies of kidney mass manipulation in a rat kidney transplant model, Barry Brenner and his colleagues postulated that augmenting the number of viable nephrons in kidney transplantation to meet the recipient’s metabolic and excretory demands may protect against long-term graft loss. This enlightening idea set the stage for the development and worldwide implementation of dual kidney transplant programs using organs from marginal—including older—donors. This concept was then complemented by robust clinical evidence that showed that a scoring system for pretransplant graft biopsies enabled the successful selection and allocation of kidneys from marginal donors for single or dual transplantation. Although these strategies have contributed significantly to expanding the kidney donor pool, the gap between supply and demand remains large, and closing it will likely require new sources, such as xenotransplantation.” Giuseppe Remuzzi</div></div><div>“In 1993, based on findings from their experimental studies of kidney mass manipulation in a rat kidney transplant model, Barry Brenner and his colleagues postulated that augmenting the number of viable nephrons in kidney transplantation to meet the recipient’s metabolic and excretory demands may protect against long-term graft loss. This enlightening idea set the stage for the development and worldwide implementation of dual kidney transplant programs using organs from marginal—including older—donors. This concept was then complemented by robust clinical evidence that showed that a scoring system for pretransplant graft biopsies enabled the successful selection and allocation of kidneys from marginal donors for single or dual transplantation. Although these strategies have contributed significantly to expanding the kidney donor pool, the gap between supply and demand remains large, and closing it will likely require new sources, such as xenotransplantation.” Giuseppe Remuzzi</div>","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"46 2","pages":"Article 151687"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147309928","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":"Kidney Injury Molecule-1: A Biomarker, Signalling Mediator, and Therapeutic Target","authors":"Ahmed Soliman PhD,&nbsp;Takaharu Ichimura PhD,&nbsp;Joseph V. Bonventre MD, PhD","doi":"10.1016/j.semnephrol.2026.151724","DOIUrl":"10.1016/j.semnephrol.2026.151724","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Kidney injury molecule 1 (KIM-1), encoded by &lt;em&gt;HAVCR1&lt;/em&gt;, was initially identified as one of the most highly induced proteins in injured proximal tubule epithelial cells and subsequently established as a sensitive tissue, urinary, and circulating biomarker of kidney injury. Yet KIM-1 is not just a marker of epithelial damage. It is a phosphatidylserine receptor that enables injured proximal tubule cells to recognize and internalize apoptotic cells and luminal cargo. This process engages intracellular trafficking, autophagy-related processing, and immune regulatory pathways, with consequences that are highly context-dependent. Transient KIM-1 expression can promote debris clearance and limit inflammation after acute injury, whereas sustained expression and uptake of protein- and lipid-rich cargo can contribute to cellular stress, maladaptive repair, inflammation, and fibrosis. Beyond kidney injury, KIM-1 is expressed and shed by renal cell carcinomas, in which circulating levels carry diagnostic, prognostic, and potentially treatment-stratifying information. KIM-1 is also emerging as both a molecular address for targeted therapeutic delivery and a candidate for functional inhibition or degradation. This review traces how KIM-1 evolved from an injury-induced transcript to a biomarker, signaling receptor, disease mediator, and therapeutic target. We propose a framework in which expression duration, cargo identity, receptor processing, intracellular trafficking, and disease context determine whether KIM-1 supports repair or promotes pathology, highlighting unresolved questions essential for translating its complex biology into more precise diagnostic and therapeutic strategies.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;Kidney injury molecule 1 (KIM-1), encoded by &lt;em&gt;HAVCR1&lt;/em&gt;, was initially identified as one of the most highly induced proteins in injured proximal tubule epithelial cells and subsequently established as a sensitive tissue, urinary, and circulating biomarker of kidney injury. Yet KIM-1 is not just a marker of epithelial damage. It is a phosphatidylserine receptor that enables injured proximal tubule cells to recognize and internalize apoptotic cells and luminal cargo. This process engages intracellular trafficking, autophagy-related processing, and immune regulatory pathways, with consequences that are highly context-dependent. Transient KIM-1 expression can promote debris clearance and limit inflammation after acute injury, whereas sustained expression and uptake of protein- and lipid-rich cargo can contribute to cellular stress, maladaptive repair, inflammation, and fibrosis. Beyond kidney injury, KIM-1 is expressed and shed by renal cell carcinomas, in which circulating levels carry diagnostic, prognostic, and potentially treatment-stratifying information. KIM-1 is also emerging as both a molecular address for targeted therapeutic delivery and a candidate for functional inhibition or degradation. This review traces how KIM-1 evolved from an i","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"46 2","pages":"Article 151724"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148971171","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":"Neuroimmune Regulation for Acute Kidney Injury Therapy: Insights Along the Path From Bench to Bedside","authors":"William T. Nash PhD ,&nbsp;Mark D. Okusa MD","doi":"10.1016/j.semnephrol.2025.151674","DOIUrl":"10.1016/j.semnephrol.2025.151674","url":null,"abstract":"<div><div>Over the past 25 years, neuroimmune regulation has emerged as a compelling approach to the prevention and treatment of acute kidney injury. Vagus nerve stimulation through the cholinergic anti-inflammatory pathway can suppress inflammatory responses and demonstrate therapeutic potential in both animal disease models and a variety of human inflammatory conditions. The mechanisms underlying this neuroimmune-regulated protection are complex, but research undertaken since 2000 has significantly advanced our understanding of the key elements involved. This research has also yielded intriguing results and unexpected observations. In this review, we highlight current insights into vagus nerve–mediated neuroimmune regulation, areas of ongoing uncertainty, and promising directions for therapeutic modulation in AKI.</div></div>","PeriodicalId":21756,"journal":{"name":"Seminars in nephrology","volume":"46 1","pages":"Article 151674"},"PeriodicalIF":3.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145259175","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}