Pub Date : 2026-01-01DOI: 10.1016/j.kint.2025.08.030
Hao Du , Baihai Jiao , Jian Xing , Dong Yang , Melanie Tran , Penghua Wang , Zhaoyong Hu , Véronique Lefebvre , Dong Zhou , Yanlin Wang
Introduction
Chronic kidney disease (CKD) is a widely prevalent health issue globally. A striking pathological feature of CKD is kidney fibrosis characterized by excessive production and deposition of extracellular matrix (ECM). Tubular epithelial cell (TEC) dedifferentiation and fibroblast activation contribute to the pathogenesis of kidney fibrosis. However, the molecular mechanisms underlying TEC dedifferentiation and fibroblast activation are not fully understood. Here, we investigated the role of SRY-box transcription factor 4 (SOX4) in regulating TEC dedifferentiation and fibroblast activation during the development of CKD.
Methods
We generated global, TEC-specific, and fibroblast-specific SOX4 knockout mice. These mice were subjected to three preclinical models of kidney fibrosis induced by unilateral ureteral obstruction, ischemia-reperfusion injury, or high-dose folic acid to examine the role of SOX4 in TEC dedifferentiation and fibroblast activation during the development of kidney fibrosis. Cultured TECs and fibroblasts were employed to determine the role and molecular mechanisms of SOX4 in regulating TEC dedifferentiation and fibroblast activation in vitro.
Results
SOX4 was induced in the injured kidneys but its deficiency inhibits TEC dedifferentiation, fibroblast activation and further impeded the development of kidney fibrosis in mice. In vitro, knockdown of SOX4 preserved the epithelial phenotype and inhibited fibroblast activation induced by transforming growth factor-β1 (TGF-β1). Mechanistically, SOX4 facilitated the TGF-β1-Smad3 signaling pathway to promote TEC dedifferentiation and fibroblast activation.
Conclusions
Our findings identify SOX4 as a critical factor in TEC dedifferentiation and fibroblast activation suggesting SOX4 may serve as a potential therapeutic target for the treatment of CKD.
{"title":"Critical role of transcription factor SOX4 in tubular epithelial cell dedifferentiation and fibroblast activation during kidney fibrosis","authors":"Hao Du , Baihai Jiao , Jian Xing , Dong Yang , Melanie Tran , Penghua Wang , Zhaoyong Hu , Véronique Lefebvre , Dong Zhou , Yanlin Wang","doi":"10.1016/j.kint.2025.08.030","DOIUrl":"10.1016/j.kint.2025.08.030","url":null,"abstract":"<div><h3>Introduction</h3><div>Chronic kidney disease (CKD) is a widely prevalent health issue globally. A striking pathological feature of CKD is kidney fibrosis characterized by excessive production and deposition of extracellular matrix (ECM). Tubular epithelial cell (TEC) dedifferentiation and fibroblast activation contribute to the pathogenesis of kidney fibrosis. However, the molecular mechanisms underlying TEC dedifferentiation and fibroblast activation are not fully understood. Here, we investigated the role of SRY-box transcription factor 4 (SOX4) in regulating TEC dedifferentiation and fibroblast activation during the development of CKD.</div></div><div><h3>Methods</h3><div>We generated global, TEC-specific, and fibroblast-specific SOX4 knockout mice. These mice were subjected to three preclinical models of kidney fibrosis induced by unilateral ureteral obstruction, ischemia-reperfusion injury, or high-dose folic acid to examine the role of SOX4 in TEC dedifferentiation and fibroblast activation during the development of kidney fibrosis. Cultured TECs and fibroblasts were employed to determine the role and molecular mechanisms of SOX4 in regulating TEC dedifferentiation and fibroblast activation <em>in vitro</em>.</div></div><div><h3>Results</h3><div>SOX4 was induced in the injured kidneys but its deficiency inhibits TEC dedifferentiation, fibroblast activation and further impeded the development of kidney fibrosis in mice. <em>In vitro</em>, knockdown of SOX4 preserved the epithelial phenotype and inhibited fibroblast activation induced by transforming growth factor-β1 (TGF-β1). Mechanistically, SOX4 facilitated the TGF-β1-Smad3 signaling pathway to promote TEC dedifferentiation and fibroblast activation.</div></div><div><h3>Conclusions</h3><div>Our findings identify SOX4 as a critical factor in TEC dedifferentiation and fibroblast activation suggesting SOX4 may serve as a potential therapeutic target for the treatment of CKD.</div></div>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages 101-118"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153429","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}
Pub Date : 2026-01-01DOI: 10.1016/j.kint.2025.09.027
Meei-Hua Lin , Kohei Omachi , Joshua F. Begin , Jennifer L. Richardson , Jeffrey H. Miner
Introduction
Alport syndrome features a defective glomerular basement membrane (GBM) due to variants in COL4A3, COL4A4, and COL4A5. The most severe forms, which lack the GBM’s collagen α3α4α5(IV) network, progress from hematuria in early childhood to proteinuria, chronic kidney disease, and kidney failure by the age of ∼30. As a monogenic disease without specific treatments, and with podocytes being the only glomerular cells that synthesize collagen α3α4α5(IV), the ability to efficiently deliver genes to Alport podocytes could open up new possibilities for treatment.
Methods
As a proof-of-concept study, we investigated whether podocytes in X-linked Alport mice were susceptible to transduction by adeno-associated virus (AAV)9. ssAAV9-CAG-tdTomato and scAAV9-CMV-Cre were intravenously injected into Col4a5-/y and Col4a5-/y; Ai14 (Cre-activatable tdTomato) Alport mice, respectively. The kidneys were collected two weeks later and subjected to quantification of podocyte transduction by fluorescence assays using synaptopodin as a podocyte marker.
Results
ssAAV9-CAG-tdTomato delivered to controls failed to transduce podocytes, but heterozygous female and hemizygous male Alport podocytes showed a range of transduction efficiencies, from 1.8% to 26%, which correlated positively with levels of albuminuria. Similar correlation between podocyte transduction and albuminuria was observed in the more sensitive Ai14 system with scAAV9-CMV-Cre administration. A subset of tubular and mesangial cells could also be transduced, the former in Alport mice and the latter in both Alport and control mice.
Conclusions
The Alport GBM becomes leaky to AAV9 as mice mature, allowing viruses to reach and transduce a substantial subset of podocytes. This is promising for someday using AAV9 or other vehicles in gene therapy for patients with Alport syndrome. Interestingly, mesangial cells of control and young Alport mice were moderately susceptible to transduction, demonstrating that gene delivery to mesangial cells in mice is a viable approach for investigating mesangial cell biology in any context.
{"title":"Mouse Alport podocytes are susceptible to AAV9 transduction in vivo","authors":"Meei-Hua Lin , Kohei Omachi , Joshua F. Begin , Jennifer L. Richardson , Jeffrey H. Miner","doi":"10.1016/j.kint.2025.09.027","DOIUrl":"10.1016/j.kint.2025.09.027","url":null,"abstract":"<div><h3>Introduction</h3><div>Alport syndrome features a defective glomerular basement membrane (GBM) due to variants in <em>COL4A3</em>, <em>COL4A4</em>, and <em>COL4A5</em>. The most severe forms, which lack the GBM’s collagen α3α4α5(IV) network, progress from hematuria in early childhood to proteinuria, chronic kidney disease, and kidney failure by the age of ∼30. As a monogenic disease without specific treatments, and with podocytes being the only glomerular cells that synthesize collagen α3α4α5(IV), the ability to efficiently deliver genes to Alport podocytes could open up new possibilities for treatment.</div></div><div><h3>Methods</h3><div>As a proof-of-concept study, we investigated whether podocytes in X-linked Alport mice were susceptible to transduction by adeno-associated virus (AAV)9. ssAAV9-CAG-tdTomato and scAAV9-CMV-Cre were intravenously injected into <em>Col4a5</em><sup><em>-/y</em></sup> and <em>Col4a5</em><sup><em>-/y</em></sup>; Ai14 (Cre-activatable tdTomato) Alport mice, respectively. The kidneys were collected two weeks later and subjected to quantification of podocyte transduction by fluorescence assays using synaptopodin as a podocyte marker.</div></div><div><h3>Results</h3><div>ssAAV9-CAG-tdTomato delivered to controls failed to transduce podocytes, but heterozygous female and hemizygous male Alport podocytes showed a range of transduction efficiencies, from 1.8% to 26%, which correlated positively with levels of albuminuria. Similar correlation between podocyte transduction and albuminuria was observed in the more sensitive Ai14 system with scAAV9-CMV-Cre administration. A subset of tubular and mesangial cells could also be transduced, the former in Alport mice and the latter in both Alport and control mice.</div></div><div><h3>Conclusions</h3><div>The Alport GBM becomes leaky to AAV9 as mice mature, allowing viruses to reach and transduce a substantial subset of podocytes. This is promising for someday using AAV9 or other vehicles in gene therapy for patients with Alport syndrome. Interestingly, mesangial cells of control and young Alport mice were moderately susceptible to transduction, demonstrating that gene delivery to mesangial cells in mice is a viable approach for investigating mesangial cell biology in any context.</div></div>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages 129-138"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145412272","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}
Pub Date : 2025-12-30DOI: 10.1016/j.kint.2025.11.018
Ivy A Rosales, Alessia Giarraputo, Claire Trivin-Avillach, Ahmad Karadagi, Christina Laguerre, Toru Goto, Jeremy Marcin, Nicole Brousaides, Tatsuo Kawai, Robert B Colvin
Introduction: Porcine xenografts are a potential future organ source. Limited short-term clinical studies have suggested different mechanisms in xenografts than allografts. Here, we sought further insights from transcript analysis of xenografts in non-human primates that achieved up to two years of survival.
Methods: Transcript analysis was performed on 58 samples from eGenesis pig kidney xenografts in Cynomolgus monkeys, including donor, post-perfusion, protocol, and terminal samples, using the Banff Human Organ Transplant panel, supplemented with 35 pig specific probes. Glomerular regions of interest in donor and terminal samples were analyzed using the GeoMx Immune Pathways Panel and 10 custom probes. Antibodies that distinguish donor and recipient molecules were used to confirm protein expression.
Results: Protocol biopsies with no histologic evidence of rejection had a marked rise in CD45 transcripts compared with donor samples, similar to CD45 levels in stable human allografts that did not portend rejection. Terminal samples showed increases in antibody and T cell mediated rejection gene sets and prominence of alternatively activated macrophages. Reduction of VEGFA transcripts correlated with transplant glomerulopathy and glomerular thrombotic microangiopathy and was localized to glomeruli by spatial transcriptomics. Loss of donor and gain of recipient endothelial transcripts were detected in the graft, with widespread expression of recipient PECAM1, vWF, and MHC class I and II proteins in xenograft endothelium.
Conclusions: Marked transcript elevation occurred in stable grafts probably due to repopulation by recipient leukocytes. VEGFA loss in podocytes preceded and potentially contributed to thrombotic microangiopathy. Loss of donor endothelial transcripts contrasts with antibody mediated rejection in allografts. Unexpected gain of recipient endothelial transcripts and proteins was shown, a novel process detected in the xenograft.
{"title":"Mechanistic insights from transcript analysis of long-term pig to non-human primate kidney xenografts.","authors":"Ivy A Rosales, Alessia Giarraputo, Claire Trivin-Avillach, Ahmad Karadagi, Christina Laguerre, Toru Goto, Jeremy Marcin, Nicole Brousaides, Tatsuo Kawai, Robert B Colvin","doi":"10.1016/j.kint.2025.11.018","DOIUrl":"10.1016/j.kint.2025.11.018","url":null,"abstract":"<p><strong>Introduction: </strong>Porcine xenografts are a potential future organ source. Limited short-term clinical studies have suggested different mechanisms in xenografts than allografts. Here, we sought further insights from transcript analysis of xenografts in non-human primates that achieved up to two years of survival.</p><p><strong>Methods: </strong>Transcript analysis was performed on 58 samples from eGenesis pig kidney xenografts in Cynomolgus monkeys, including donor, post-perfusion, protocol, and terminal samples, using the Banff Human Organ Transplant panel, supplemented with 35 pig specific probes. Glomerular regions of interest in donor and terminal samples were analyzed using the GeoMx Immune Pathways Panel and 10 custom probes. Antibodies that distinguish donor and recipient molecules were used to confirm protein expression.</p><p><strong>Results: </strong>Protocol biopsies with no histologic evidence of rejection had a marked rise in CD45 transcripts compared with donor samples, similar to CD45 levels in stable human allografts that did not portend rejection. Terminal samples showed increases in antibody and T cell mediated rejection gene sets and prominence of alternatively activated macrophages. Reduction of VEGFA transcripts correlated with transplant glomerulopathy and glomerular thrombotic microangiopathy and was localized to glomeruli by spatial transcriptomics. Loss of donor and gain of recipient endothelial transcripts were detected in the graft, with widespread expression of recipient PECAM1, vWF, and MHC class I and II proteins in xenograft endothelium.</p><p><strong>Conclusions: </strong>Marked transcript elevation occurred in stable grafts probably due to repopulation by recipient leukocytes. VEGFA loss in podocytes preceded and potentially contributed to thrombotic microangiopathy. Loss of donor endothelial transcripts contrasts with antibody mediated rejection in allografts. Unexpected gain of recipient endothelial transcripts and proteins was shown, a novel process detected in the xenograft.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889518","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}
Pub Date : 2025-12-30DOI: 10.1016/j.kint.2025.12.018
Kensei Taguchi, Kei Fukami
{"title":"Key drivers and potential therapeutic targets in the AKI-to-CKD transition: roles of kidney-resident macrophages and neutrophils.","authors":"Kensei Taguchi, Kei Fukami","doi":"10.1016/j.kint.2025.12.018","DOIUrl":"10.1016/j.kint.2025.12.018","url":null,"abstract":"","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":" ","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889512","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}
INTRODUCTIONPost-kidney transplant (KT) hyperparathyroidism (PT-HPT) is common and linked to adverse outcomes, yet the contributions of calcium bioavailability and parathyroid responsiveness remain poorly defined. Here, we studied the trajectory of oral calcium-mediated PTH suppression (CMPS) in PT-HPT and its association with PTH control in the first year post-KT.METHODSThis single-center prospective cohort study evaluated 657 KT recipients at 3 (M3) and 12 (M12) months post-KT with an oral calcium loading test, and assessed measured glomerular filtration rate (mGFR), bone turnover markers, and dual X-ray absorptiometry.RESULTSAt M3, hyperparathyroidism was evident in 71% patients, with a median CMPS of 31%. Impaired PTH suppression was associated with blunted increases in ionized calcium in 30% of patients, suggesting impaired intestinal calcium absorption. Despite a decline in mGFR over time, calcium-PTH dynamics improved by M12, with a leftward shift in the curve across all groups. Patients with higher baseline CMPS had significantly lower PTH at M12 (87 vs. 99 pg/ml), despite higher initial PTH and less frequent calcimimetic use (5.5% vs. 12%). Bone mineral density increased across all groups, with greater gain at the hip than the lumbar spine in patients with higher baseline PTH suppression. Higher baseline CMPS was independently associated with lower M12 PTH levels, after adjusting for potential confounders. The association remained significant in a sensitivity analysis excluding patients with blunted increases in serum ionized or urinary calcium suggestive of calcium absorption.CONCLUSIONSOral calcium-mediated PTH suppression at M3 post-KT was linked to lower PTH levels at one year, suggesting that both parathyroid gland responsiveness and calcium bioavailability are associated with favorable outcomes in PT-HPT. This test may also help stratifying PT-HPT subtypes for tailored management.
{"title":"Parathyroid hormone suppression profiles following oral calcium challenge in kidney transplant recipients.","authors":"Jordan Desenclos,Caroline Halimi,Emmanuelle Vidal-Petiot,Justina Motiejunaite,Eric Daugas,Tiphaine Robert,Anne Boutten,Marie-Noëlle Peraldi,Corinne Antoine,François Vrtovsnik,Christine Randoux,Guillaume Hanouna,Quentin Raimbourg,Martin Flamant,Nahid Tabibzadeh","doi":"10.1016/j.kint.2025.11.019","DOIUrl":"https://doi.org/10.1016/j.kint.2025.11.019","url":null,"abstract":"INTRODUCTIONPost-kidney transplant (KT) hyperparathyroidism (PT-HPT) is common and linked to adverse outcomes, yet the contributions of calcium bioavailability and parathyroid responsiveness remain poorly defined. Here, we studied the trajectory of oral calcium-mediated PTH suppression (CMPS) in PT-HPT and its association with PTH control in the first year post-KT.METHODSThis single-center prospective cohort study evaluated 657 KT recipients at 3 (M3) and 12 (M12) months post-KT with an oral calcium loading test, and assessed measured glomerular filtration rate (mGFR), bone turnover markers, and dual X-ray absorptiometry.RESULTSAt M3, hyperparathyroidism was evident in 71% patients, with a median CMPS of 31%. Impaired PTH suppression was associated with blunted increases in ionized calcium in 30% of patients, suggesting impaired intestinal calcium absorption. Despite a decline in mGFR over time, calcium-PTH dynamics improved by M12, with a leftward shift in the curve across all groups. Patients with higher baseline CMPS had significantly lower PTH at M12 (87 vs. 99 pg/ml), despite higher initial PTH and less frequent calcimimetic use (5.5% vs. 12%). Bone mineral density increased across all groups, with greater gain at the hip than the lumbar spine in patients with higher baseline PTH suppression. Higher baseline CMPS was independently associated with lower M12 PTH levels, after adjusting for potential confounders. The association remained significant in a sensitivity analysis excluding patients with blunted increases in serum ionized or urinary calcium suggestive of calcium absorption.CONCLUSIONSOral calcium-mediated PTH suppression at M3 post-KT was linked to lower PTH levels at one year, suggesting that both parathyroid gland responsiveness and calcium bioavailability are associated with favorable outcomes in PT-HPT. This test may also help stratifying PT-HPT subtypes for tailored management.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"23 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145847528","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}
Pub Date : 2025-12-25DOI: 10.1016/j.kint.2025.12.014
Ayman Al Jurdi,Camille N Kotton,Richard Lafayette
Complement inhibitors are now approved for use in atypical HUS, IgA nephropathy and in C3 glomerulopathy. They are being studied widely in kidney disease, and more indications may soon arise. This review addresses an approach to preventing infectious complications, particularly encapsulated organism infections, and will hopefully serve as guidance for nephrologists utilizing these agents.
{"title":"Modern Challenges in Infection Prevention: Encapsulated Organisms in the era of novel complement inhibitors.","authors":"Ayman Al Jurdi,Camille N Kotton,Richard Lafayette","doi":"10.1016/j.kint.2025.12.014","DOIUrl":"https://doi.org/10.1016/j.kint.2025.12.014","url":null,"abstract":"Complement inhibitors are now approved for use in atypical HUS, IgA nephropathy and in C3 glomerulopathy. They are being studied widely in kidney disease, and more indications may soon arise. This review addresses an approach to preventing infectious complications, particularly encapsulated organism infections, and will hopefully serve as guidance for nephrologists utilizing these agents.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"11 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844823","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}
Older patients represent the most rapidly growing age-group presenting with kidney failure. Despite this high incidence, the rate of progression to kidney failure tends to be slower in older individuals, and the competing risk of death before the development of kidney failure is a more significant consideration in older patients compared with younger counterparts. Incorporating these concepts of risk are challenging in shared decision-making discussions between clinicians, older patients and their families. Risk prediction models are rapidly increasing in nephrology and have the potential to provide personalized absolute risk prediction for patients with advanced chronic kidney disease (CKD), however there are several considerations of these models relevant to older patient populations. This review discusses metrics for assessing risk prediction models, examines key models for predicting kidney failure and mortality risk in older patients with advanced CKD, and provides guidance for how best to interpret and utilize these models to support personalized decision-making processes with older patients.
{"title":"UTILIZING RISK PREDICTION MODELS FOR OLDER PATIENTS WITH CHRONIC KIDNEY DISEASE.","authors":"Amanda Siriwardana,Navdeep Tangri,Brendon Neuen,Meg Jardine,Celine Foote,Martin Gallagher","doi":"10.1016/j.kint.2025.11.021","DOIUrl":"https://doi.org/10.1016/j.kint.2025.11.021","url":null,"abstract":"Older patients represent the most rapidly growing age-group presenting with kidney failure. Despite this high incidence, the rate of progression to kidney failure tends to be slower in older individuals, and the competing risk of death before the development of kidney failure is a more significant consideration in older patients compared with younger counterparts. Incorporating these concepts of risk are challenging in shared decision-making discussions between clinicians, older patients and their families. Risk prediction models are rapidly increasing in nephrology and have the potential to provide personalized absolute risk prediction for patients with advanced chronic kidney disease (CKD), however there are several considerations of these models relevant to older patient populations. This review discusses metrics for assessing risk prediction models, examines key models for predicting kidney failure and mortality risk in older patients with advanced CKD, and provides guidance for how best to interpret and utilize these models to support personalized decision-making processes with older patients.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"10 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145836045","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}
Pub Date : 2025-12-24DOI: 10.1016/j.kint.2025.12.013
Janewit Wongboonsin,Kristen M Gibson,Juntao Ke,Zachary Sentell,Juliana E Arcila Galvis,Satoshi Koyama,Anya Greenberg,Kaylia Reynolds,Giovanni Montini,Riccardo Magistroni,Adele Mitrotti,Loreto Gesualdo,Alessandro Pezzuto,Licia Peruzzi,Yasar Caliskan,Ana C Onuchic-Whitford,Srichan Bunlungsup,Michelle McNulty,Rasheed Gbadegesin,Moin A Saleem,Martin R Pollak,Friedhelm Hildebrandt,Pradeep Natarajan,Dongwon Lee,Sagar U Nigwekar,John A Sayer,Simone Sanna-Cherchi,Matthew G Sampson
INTRODUCTIONHealth system-based biobanks with genetic data provide a unique opportunity for nephrotic syndrome (NS) genomic discovery. This is predicated on finding cases in the electronic-health-record.METHODSWe tested three strategies to identify focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD) cases in the 130,000 member of Mass-General-Brigham-Biobank (MGBB). We analyzed a "synthetic proteinuria panel" of 192 Mendelian genes and the APOL1 kidney risk variants in those with exome sequencing (ES). We studied the associations between patients with Mendelian variants (MV), APOL1-HR genotype (APOL1) and outcomes. Validation of a novel gene-FSGS association was done in the Genomics England 100,000 Genome Project (100KG) and a global NS case-control cohort.RESULTS319 MGBB participants had FSGS or MCD and ES data; reviewing pathology reports was the most accurate screening strategy. 31(9.7%) of patients had MV and 24(7.5%) had APOL1. 61% of genetic NS with a kidney biopsy report were classified as secondary FSGS. MV and APOL1 patients had a 3.1(1.1-8.7) and 6.5(1.3-32.3) increased odds of developing kidney failure, respectively. Unexpectedly, monoallelic pathogenic variants in MEFV (Mendelian gene for Familial Mediterranean Fever [FMF]) were found in 6 MGBB participants with FSGS, all of whom had features of collapsing glomerulopathy and thrombotic microangiopathy. 8 glomerular disease cases in the 100KG, unsolved via genome sequencing, had monoallelic pathogenic MEFV variants. Finally, a case-control study found a 3.8 increased odds of SRNS in individuals with pathogenic or likely pathogenic MEFV alleles (P = 7.8 x10-5).CONCLUSION17.2% of unselected adults with NS in the MGBB had a well-established genetic form, each associated with an increased risk of kidney failure. A biopsy read of secondary FSGS should not be used to rule out testing for genetic disease. Monoallelic pathogenic variants in MEFV may be a novel and underappreciated cause or susceptibility factor for SRNS/FSGS with distinct histologic features, even in the absence of clinical FMF.
{"title":"Nephrotic syndrome genomic discovery in the Mass General Brigham Biobank identifies monoallelic MEFV variants as a risk factor for focal segmental glomerulosclerosis.","authors":"Janewit Wongboonsin,Kristen M Gibson,Juntao Ke,Zachary Sentell,Juliana E Arcila Galvis,Satoshi Koyama,Anya Greenberg,Kaylia Reynolds,Giovanni Montini,Riccardo Magistroni,Adele Mitrotti,Loreto Gesualdo,Alessandro Pezzuto,Licia Peruzzi,Yasar Caliskan,Ana C Onuchic-Whitford,Srichan Bunlungsup,Michelle McNulty,Rasheed Gbadegesin,Moin A Saleem,Martin R Pollak,Friedhelm Hildebrandt,Pradeep Natarajan,Dongwon Lee,Sagar U Nigwekar,John A Sayer,Simone Sanna-Cherchi,Matthew G Sampson","doi":"10.1016/j.kint.2025.12.013","DOIUrl":"https://doi.org/10.1016/j.kint.2025.12.013","url":null,"abstract":"INTRODUCTIONHealth system-based biobanks with genetic data provide a unique opportunity for nephrotic syndrome (NS) genomic discovery. This is predicated on finding cases in the electronic-health-record.METHODSWe tested three strategies to identify focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD) cases in the 130,000 member of Mass-General-Brigham-Biobank (MGBB). We analyzed a \"synthetic proteinuria panel\" of 192 Mendelian genes and the APOL1 kidney risk variants in those with exome sequencing (ES). We studied the associations between patients with Mendelian variants (MV), APOL1-HR genotype (APOL1) and outcomes. Validation of a novel gene-FSGS association was done in the Genomics England 100,000 Genome Project (100KG) and a global NS case-control cohort.RESULTS319 MGBB participants had FSGS or MCD and ES data; reviewing pathology reports was the most accurate screening strategy. 31(9.7%) of patients had MV and 24(7.5%) had APOL1. 61% of genetic NS with a kidney biopsy report were classified as secondary FSGS. MV and APOL1 patients had a 3.1(1.1-8.7) and 6.5(1.3-32.3) increased odds of developing kidney failure, respectively. Unexpectedly, monoallelic pathogenic variants in MEFV (Mendelian gene for Familial Mediterranean Fever [FMF]) were found in 6 MGBB participants with FSGS, all of whom had features of collapsing glomerulopathy and thrombotic microangiopathy. 8 glomerular disease cases in the 100KG, unsolved via genome sequencing, had monoallelic pathogenic MEFV variants. Finally, a case-control study found a 3.8 increased odds of SRNS in individuals with pathogenic or likely pathogenic MEFV alleles (P = 7.8 x10-5).CONCLUSION17.2% of unselected adults with NS in the MGBB had a well-established genetic form, each associated with an increased risk of kidney failure. A biopsy read of secondary FSGS should not be used to rule out testing for genetic disease. Monoallelic pathogenic variants in MEFV may be a novel and underappreciated cause or susceptibility factor for SRNS/FSGS with distinct histologic features, even in the absence of clinical FMF.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"17 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145836110","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}
Despite important advances over the past decades, chronic kidney disease-mineral and bone disorder (CKD-MBD) remains a major clinical therapeutic challenge. Traditional interventions targeting hyperphosphatemia, impaired vitamin D metabolism, and secondary hyperparathyroidism overall failed to meet expectations. This calls for a paradigm shift. The 2023 Madrid CKD-MBD Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference advocated a holistic approach to replace current parathyroid hormone-calcium-phosphate centric approach. In this context, the FGF23-α-Klotho axis has emerged as a key regulator of mineral metabolism and a potential novel therapeutic target. In parallel, meta-organismal tryptophan dysmetabolism recently gained interest as a novel pathogenic driver of both CKD-associated osteoporosis and cardiovascular disease. CKD not only profoundly disturbs microbial and endogenous tryptophan metabolism, but also causes accumulation of tryptophan metabolites, some of which are increasingly recognized as uremic toxins, including indoxyl sulphate, kynurenine and kynurenic acid. They may confer cardiovascular and skeletal toxicity either by inducing direct cellular toxicity or by activating the aryl hydrocarbon receptor (AhR). While adding another level of complexity to the pathogenesis of CKD-MBD, these insights also create novel therapeutic opportunities.
{"title":"Meta-organismal tryptophan metabolism: an appealing therapeutic target in CKD-MBD.","authors":"Guillaume Fernandes,Stéphane Burtey,Ward Zadora,Bjorn Meijers,Dieter Smout,Laura Labriola,Pieter Evenepoel","doi":"10.1016/j.kint.2025.11.022","DOIUrl":"https://doi.org/10.1016/j.kint.2025.11.022","url":null,"abstract":"Despite important advances over the past decades, chronic kidney disease-mineral and bone disorder (CKD-MBD) remains a major clinical therapeutic challenge. Traditional interventions targeting hyperphosphatemia, impaired vitamin D metabolism, and secondary hyperparathyroidism overall failed to meet expectations. This calls for a paradigm shift. The 2023 Madrid CKD-MBD Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference advocated a holistic approach to replace current parathyroid hormone-calcium-phosphate centric approach. In this context, the FGF23-α-Klotho axis has emerged as a key regulator of mineral metabolism and a potential novel therapeutic target. In parallel, meta-organismal tryptophan dysmetabolism recently gained interest as a novel pathogenic driver of both CKD-associated osteoporosis and cardiovascular disease. CKD not only profoundly disturbs microbial and endogenous tryptophan metabolism, but also causes accumulation of tryptophan metabolites, some of which are increasingly recognized as uremic toxins, including indoxyl sulphate, kynurenine and kynurenic acid. They may confer cardiovascular and skeletal toxicity either by inducing direct cellular toxicity or by activating the aryl hydrocarbon receptor (AhR). While adding another level of complexity to the pathogenesis of CKD-MBD, these insights also create novel therapeutic opportunities.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"19 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145830318","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}
Pub Date : 2025-12-23DOI: 10.1016/j.kint.2025.12.012
Dong-U Shin,Min Kyoung Jo,Minjeong Kwon,Yewon Jeong,Bogyeong Cho,Seong A Kim,Ga-Eun Choi,Seohyun Kim,Seok Ho Song,Hyemin Joo,Hyun Jung Kim,Jung Pyo Lee,Jeonghwan Lee,In-San Kim,Gi-Hoon Nam
INTRODUCTIONAcute kidney injury (AKI) presents significant clinical challenges, with high mortality and progression risk to chronic kidney disease. Mechanisms remain incompletely understood and disease-specific therapies are lacking. Recent evidence highlights the pivotal role of infiltrating myeloid cells in perpetuating kidney inflammation. CD47, a key cell surface immune checkpoint protein, is upregulated in inflammation and regulates myeloid cell infiltration, making it an attractive therapeutic target.METHODSSingle-cell RNA sequencing and CD47 protein staining were used to identify CD47 expressions in human AKI specimens and two mouse models (cis-platin and bilateral ischemia/reperfusion). To therapeutically exploit this, we engineered extracellular vesicles (EVs) from human bone marrow mesenchymal stem cells to express a high-affinity signal regulatory protein a (SIRPα) variant (SIRP-EVs), the ligand for CD47. The efficacy of SIRP-EVs was evaluated in murine AKI models.RESULTSCD47 expression was significantly elevated in myeloid populations, particularly macrophages, in both human AKI tissues and mouse models. A single systemic administration of SIRP-EVs in murine AKI models exhibited therapeutic effects, including improved kidney function markers, reduced pro-inflammatory cytokine production, and ameliorated kidney histopathology. Mechanistically, SIRP-EVs preferentially localize to circulating myeloid cells, modulate CD47 expression, and subsequently inhibit their migration into injured kidney tissue. Moreover, single cell transcriptomics revealed that SIRP-EV treatment reprograms circulating macrophages toward pro-resolving phenotypes, characterized by upregulation of genes associated with tissue repair.CONCLUSIONSTargeting CD47 on circulating myeloid cells with SIRP-EVs provides a systemic, blood focused immunomodulatory strategy that precedes tissue infiltration, contrasting with conventional tissue-centric approaches. Our findings support SIRP-EVs as a promising therapeutic option for AKI and potentially other inflammation-driven diseases through selective modulation and reprogramming of peripheral myeloid cells.
{"title":"Therapeutic reprogramming of circulating myeloid cells via signal regulatory protein α extracellular vesicles in acute kidney injury.","authors":"Dong-U Shin,Min Kyoung Jo,Minjeong Kwon,Yewon Jeong,Bogyeong Cho,Seong A Kim,Ga-Eun Choi,Seohyun Kim,Seok Ho Song,Hyemin Joo,Hyun Jung Kim,Jung Pyo Lee,Jeonghwan Lee,In-San Kim,Gi-Hoon Nam","doi":"10.1016/j.kint.2025.12.012","DOIUrl":"https://doi.org/10.1016/j.kint.2025.12.012","url":null,"abstract":"INTRODUCTIONAcute kidney injury (AKI) presents significant clinical challenges, with high mortality and progression risk to chronic kidney disease. Mechanisms remain incompletely understood and disease-specific therapies are lacking. Recent evidence highlights the pivotal role of infiltrating myeloid cells in perpetuating kidney inflammation. CD47, a key cell surface immune checkpoint protein, is upregulated in inflammation and regulates myeloid cell infiltration, making it an attractive therapeutic target.METHODSSingle-cell RNA sequencing and CD47 protein staining were used to identify CD47 expressions in human AKI specimens and two mouse models (cis-platin and bilateral ischemia/reperfusion). To therapeutically exploit this, we engineered extracellular vesicles (EVs) from human bone marrow mesenchymal stem cells to express a high-affinity signal regulatory protein a (SIRPα) variant (SIRP-EVs), the ligand for CD47. The efficacy of SIRP-EVs was evaluated in murine AKI models.RESULTSCD47 expression was significantly elevated in myeloid populations, particularly macrophages, in both human AKI tissues and mouse models. A single systemic administration of SIRP-EVs in murine AKI models exhibited therapeutic effects, including improved kidney function markers, reduced pro-inflammatory cytokine production, and ameliorated kidney histopathology. Mechanistically, SIRP-EVs preferentially localize to circulating myeloid cells, modulate CD47 expression, and subsequently inhibit their migration into injured kidney tissue. Moreover, single cell transcriptomics revealed that SIRP-EV treatment reprograms circulating macrophages toward pro-resolving phenotypes, characterized by upregulation of genes associated with tissue repair.CONCLUSIONSTargeting CD47 on circulating myeloid cells with SIRP-EVs provides a systemic, blood focused immunomodulatory strategy that precedes tissue infiltration, contrasting with conventional tissue-centric approaches. Our findings support SIRP-EVs as a promising therapeutic option for AKI and potentially other inflammation-driven diseases through selective modulation and reprogramming of peripheral myeloid cells.","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"35 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145830319","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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