Pub Date : 2026-01-01DOI: 10.1016/j.kint.2025.06.005
Jodie L. Babitt , Jeffrey S. Berns , Biykem Bozkurt , Rebecca S. Cheung Khedairy , Yarieli Cuevas , Emmanuel E. Effa , Michele F. Eisenga , Steven Fishbane , Yelena Z. Ginzburg , Volker H. Haase , S. Susan Hedayati , Siah Kim , José A. Moura-Neto , Evi V. Nagler , Patrick Rossignol , Manisha Sahay , Tetsuhiro Tanaka , Angela Yee-Moon Wang , David C. Wheeler , Karen A. Robinson , Marcello Tonelli
The Kidney Disease: Improving Global Outcomes (KDIGO) 2026 Clinical Practice Guideline for the Management of Anemia in Chronic Kidney Disease (CKD) represents an update to the guideline published in 2012. Its scope includes diagnosis and evaluation of anemia; use of iron to treat iron deficiency and anemia in CKD; use of erythropoiesis-stimulating agents and hypoxia-inducible factor–prolyl hydroxylase inhibitors to treat anemia in CKD; and red blood cell transfusions to treat anemia in CKD. The guideline has been developed with patient partners, healthcare providers, and researchers around the world, with the goal to generate a useful resource for healthcare providers and patients by providing actionable recommendations. The development of this guideline followed an explicit process of evidence review and appraisal based on systematic reviews. The certainty of evidence and strength of recommendations follows the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. The guideline also provides practice points that provide clinical advice but are not supported by a systematic review. Limitations of the evidence are discussed. Research recommendations to address gaps in knowledge, and implications for policy and payment, are provided. The guideline targets a broad audience of healthcare providers, affected individuals, and stakeholders involved in the various aspects of anemia and CKD care.
{"title":"Executive Summary of the KDIGO 2026 Clinical Practice Guideline for the Management of Anemia in Chronic Kidney Disease (CKD)","authors":"Jodie L. Babitt , Jeffrey S. Berns , Biykem Bozkurt , Rebecca S. Cheung Khedairy , Yarieli Cuevas , Emmanuel E. Effa , Michele F. Eisenga , Steven Fishbane , Yelena Z. Ginzburg , Volker H. Haase , S. Susan Hedayati , Siah Kim , José A. Moura-Neto , Evi V. Nagler , Patrick Rossignol , Manisha Sahay , Tetsuhiro Tanaka , Angela Yee-Moon Wang , David C. Wheeler , Karen A. Robinson , Marcello Tonelli","doi":"10.1016/j.kint.2025.06.005","DOIUrl":"10.1016/j.kint.2025.06.005","url":null,"abstract":"<div><div>The <em>Kidney Disease: Improving Global Outcomes (KDIGO) 2026 Clinical Practice Guideline for the Management of Anemia in Chronic Kidney Disease (CKD)</em> represents an update to the guideline published in 2012. Its scope includes diagnosis and evaluation of anemia; use of iron to treat iron deficiency and anemia in CKD; use of erythropoiesis-stimulating agents and hypoxia-inducible factor–prolyl hydroxylase inhibitors to treat anemia in CKD; and red blood cell transfusions to treat anemia in CKD. The guideline has been developed with patient partners, healthcare providers, and researchers around the world, with the goal to generate a useful resource for healthcare providers and patients by providing actionable recommendations. The development of this guideline followed an explicit process of evidence review and appraisal based on systematic reviews. The certainty of evidence and strength of recommendations follows the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. The guideline also provides practice points that provide clinical advice but are not supported by a systematic review. Limitations of the evidence are discussed. Research recommendations to address gaps in knowledge, and implications for policy and payment, are provided. The guideline targets a broad audience of healthcare providers, affected individuals, and stakeholders involved in the various aspects of anemia and CKD care.</div></div>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages 44-56"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145883531","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.2025.08.042
Alessia Giarraputo , Evelyn Metzger , Nicole Brousaides , Jeremy Marcin , Claire Trivin-Avillach , R. Neal Smith , Joseph M. Beechem , Ivy A. Rosales , Robert B. Colvin
Introduction
Chronic active antibody-mediated rejection (CAMR) is a leading cause of late kidney allograft dysfunction, characterized by transplant glomerulopathy involving glomerular endothelial cells (GEC), natural killer (NK) cells, and macrophages. Mechanistic understanding remains limited due to the inability of bulk and single-cell RNA techniques to capture spatial molecular interactions.
Methods
Using spatial transcriptomics at single-cell resolution (CosMx Spatial Molecular Imager), we analyzed formalin fixed paraffin embedded kidney biopsies with CAMR and compared with controls without rejection.
Results
Cell typing, clustering, and dimensionality reduction identified 36 reference cell types, while selectively localizing GEC subtypes, NK cells, and macrophages in glomeruli. Cellular differential gene expression (DGE), cell proximity, and cell-to-cell ligand-receptor analyses elucidated candidate CAMR molecular mechanisms. Spatially resolved single-cell transcriptomics revealed upregulation of intraglomerular NK cell and macrophage genes in CAMR related to cytotoxicity, IgG Fc receptor and non-self-recognition. GEC subtypes developed distinctive transcript phenotypes that included upregulated genes related to complement protection, the MHC target of donor specific antibodies and IFNγ pathway and downregulation of sialyltransferase involved in protective glycocalyx synthesis and vascular integrity. Proximity of NK cells and macrophages with GEC revealed several potential ligand receptor interactions previously unappreciated, including GEC IL33→NK cell IL1RL1 and GEC HLA-DQA1→Macrophage FCGR3A, implicating NK cell and macrophage activation in endothelial injury.
Conclusions
High-resolution spatial transcriptomics provided novel and confirmatory insights into CAMR pathogenesis, highlighting cell-specific activation states, molecular interactions, and potential mechanistic pathways involving GECs, NK cells, and macrophages. Our findings advance understanding of CAMR and identify molecular targets for further investigation.
{"title":"Single-cell spatial transcriptomics reveal intraglomerular cell activation and ligand-receptor relationships in chronic, active antibody mediated rejection","authors":"Alessia Giarraputo , Evelyn Metzger , Nicole Brousaides , Jeremy Marcin , Claire Trivin-Avillach , R. Neal Smith , Joseph M. Beechem , Ivy A. Rosales , Robert B. Colvin","doi":"10.1016/j.kint.2025.08.042","DOIUrl":"10.1016/j.kint.2025.08.042","url":null,"abstract":"<div><h3>Introduction</h3><div>Chronic active antibody-mediated rejection (CAMR) is a leading cause of late kidney allograft dysfunction, characterized by transplant glomerulopathy involving glomerular endothelial cells (GEC), natural killer (NK) cells, and macrophages. Mechanistic understanding remains limited due to the inability of bulk and single-cell RNA techniques to capture spatial molecular interactions.</div></div><div><h3>Methods</h3><div>Using spatial transcriptomics at single-cell resolution (CosMx Spatial Molecular Imager), we analyzed formalin fixed paraffin embedded kidney biopsies with CAMR and compared with controls without rejection.</div></div><div><h3>Results</h3><div>Cell typing, clustering, and dimensionality reduction identified 36 reference cell types, while selectively localizing GEC subtypes, NK cells, and macrophages in glomeruli. Cellular differential gene expression (DGE), cell proximity, and cell-to-cell ligand-receptor analyses elucidated candidate CAMR molecular mechanisms. Spatially resolved single-cell transcriptomics revealed upregulation of intraglomerular NK cell and macrophage genes in CAMR related to cytotoxicity, IgG Fc receptor and non-self-recognition. GEC subtypes developed distinctive transcript phenotypes that included upregulated genes related to complement protection, the MHC target of donor specific antibodies and IFNγ pathway and downregulation of sialyltransferase involved in protective glycocalyx synthesis and vascular integrity. Proximity of NK cells and macrophages with GEC revealed several potential ligand receptor interactions previously unappreciated, including GEC <em>IL33</em>→NK cell <em>IL1RL1</em> and GEC <em>HLA-DQA1</em>→Macrophage <em>FCGR3A</em>, implicating NK cell and macrophage activation in endothelial injury.</div></div><div><h3>Conclusions</h3><div>High-resolution spatial transcriptomics provided novel and confirmatory insights into CAMR pathogenesis, highlighting cell-specific activation states, molecular interactions, and potential mechanistic pathways involving GECs, NK cells, and macrophages. Our findings advance understanding of CAMR and identify molecular targets for further investigation.</div></div>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages 196-210"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145382745","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.2025.09.034
Andrew H. Baker , Margreet R. de Vries
Single-cell transcriptomics of arteriovenous fistulas reveal that failure is likely driven less by smooth muscle proliferation than by continuous inflammation, endothelial dysfunction, and fibroblast-driven fibrosis. These insights reframe current knowledge and highlight mechanistic pathways as to where future therapies could be targeted to improve arteriovenous fistula maturation kinetics and associated patency rates.
{"title":"Insights into arteriovenous fistula (non)maturation: single-cell transcriptomics reveals new drivers of arteriovenous fistula remodeling","authors":"Andrew H. Baker , Margreet R. de Vries","doi":"10.1016/j.kint.2025.09.034","DOIUrl":"10.1016/j.kint.2025.09.034","url":null,"abstract":"<div><div>Single-cell transcriptomics of arteriovenous fistulas reveal that failure is likely driven less by smooth muscle proliferation than by continuous inflammation, endothelial dysfunction, and fibroblast-driven fibrosis. These insights reframe current knowledge and highlight mechanistic pathways as to where future therapies could be targeted to improve arteriovenous fistula maturation kinetics and associated patency rates.</div></div>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Pages 37-40"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145883530","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.2025.07.035
Nora Abazi-Emini , Ardiana Beqiri-Jashari , Ivan Akimovski , Anja M. Billing , Markus M. Rinschen , Aleksandra Janchevska , Björn Reusch , Velibor Tasic , Bodo B. Beck
{"title":"Intermittent dark urine in a school-aged boy: a case of alkaptonuria","authors":"Nora Abazi-Emini , Ardiana Beqiri-Jashari , Ivan Akimovski , Anja M. Billing , Markus M. Rinschen , Aleksandra Janchevska , Björn Reusch , Velibor Tasic , Bodo B. Beck","doi":"10.1016/j.kint.2025.07.035","DOIUrl":"10.1016/j.kint.2025.07.035","url":null,"abstract":"","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":"109 1","pages":"Page 231"},"PeriodicalIF":12.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145883528","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.2025.08.030
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}
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