Kidney International Reports最新文献

{"title":"Heat Stress Nephropathy in CKD of Uncertain Etiology Hotspots of Bargarh District Odisha, India","authors":"Pralaya Biswas ,&nbsp;Ashish Kumar Sahu ,&nbsp;Sourav Shristi ,&nbsp;Tapan Kumar Behera ,&nbsp;Sawan Kumar Sahoo ,&nbsp;Syed Nikhat Ahmed ,&nbsp;Sarat Kumar Mohanty ,&nbsp;Sharada Shrinivas Pati ,&nbsp;Kailasam Murugesan ,&nbsp;Niranjan Mallick ,&nbsp;Pradeep Kumar Naik ,&nbsp;Sunanda Nayak ,&nbsp;Iswar Baitharu","doi":"10.1016/j.ekir.2025.07.013","DOIUrl":"10.1016/j.ekir.2025.07.013","url":null,"abstract":"<div><h3>Introduction</h3><div>Repeated heat exposure, physical exertion, and inadequate hydration can cause acute kidney injury (AKI), potentially progressing to chronic kidney disease (CKD). However, cohort-level research on heat stress as a contributing factor remains limited. This study investigates occupational heat exposure among farming communities in hotspot villages of Bargarh district, Odisha, India.</div></div><div><h3>Methods</h3><div>A cross-sectional study of 1136 participants was conducted in Bargarh district to assess heat stress nephropathy among agricultural workers. Based on Sri Lankan criteria, heat stress nephropathy was defined by albumin-creatinine ratio ≥ 30 mg/g, no known CKD causes, urine specific gravity ≥ 1.03, and signs of tubulointerstitial nephritis. Heat stress index, serological tests, and urine analyses were performed using standard protocols. Serum and urine levels of heat shock protein (HSP)27 and HSP70 were measured via enzyme-linked immunosorbent assay. Renal biopsies were conducted on 8 selected patients for histopathological evaluation.</div></div><div><h3>Results</h3><div>Out of the total screened population, 157 potential cases of heat stress nephropathy were identified, with 63.3% of affected individuals being farmers. The Attabira block recorded the highest heat stress index and the most CKD of uncertain etiology (CKDu) cases among farmers. Markers of dehydration, including the simplified wet bulb globe temperature (sWBGT) index, urine specific gravity (64.09%), albumin-to-creatinine ratio (5.88%), blood urea nitrogen (BUN, 63.2%), and HSP, were significantly elevated in the farming population compared with the control group. Renal histopathological analysis revealed tubulointerstitial nephritis with signs of fibrosis.</div></div><div><h3>Conclusion</h3><div>Heat stress nephropathy was commonly observed among individuals involved in farming activities. Renal histopathological analysis, along with elevated levels of HSP70 and HSP27 confirmed the diagnosis.</div></div>","PeriodicalId":17761,"journal":{"name":"Kidney International Reports","volume":"10 10","pages":"Pages 3379-3394"},"PeriodicalIF":5.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145242234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Canadian Stakeholders’ Perspectives on Voucher Donation in Kidney Transplantation","authors":"Aliya Affdal ,&nbsp;Marie-Françoise Malo ,&nbsp;Fabian Ballesteros ,&nbsp;Savannah-Lou Cochran-Mavrikakis ,&nbsp;Carina Sancho ,&nbsp;Marie Achille ,&nbsp;Shaifali Sandal ,&nbsp;Christy Simpson ,&nbsp;Marie-Chantal Fortin","doi":"10.1016/j.ekir.2025.06.055","DOIUrl":"10.1016/j.ekir.2025.06.055","url":null,"abstract":"<div><h3>Introduction</h3><div>Living donation remains the best therapy for people with end-stage kidney disease. Voucher donation allows donation to take place at the time that is most convenient for the donor. In this type of donation, a voucher is issued that can later be exchanged by a person in need of a kidney transplant. Voucher donation raises numerous issues. The objective of this study was to gather the perspectives of patients and transplant professionals on voucher donation.</div></div><div><h3>Methods</h3><div>We conducted interviews with 24 patients and 21 transplant professionals between November 2020 and December 2022. The interviews were digitally recorded, transcribed, and analyzed using the qualitative description approach.</div></div><div><h3>Results</h3><div>Most participants were open-minded about the possibility of implementing voucher donation because it could increase the number of available organs; however, they raised the following ethical concerns: issues of fairness, risks of undue pressure, informed consent, and risks of commodification. Prioritization among voucher holders, the number of vouchers allowed, the transferability of vouchers, and the verification of voucher holder’s identity were the logistical issues raised. Actions suggested before implementing this program included the following: a regulatory framework or guidelines, educational tools, patient engagement, and management by a national program.</div></div><div><h3>Conclusion</h3><div>This study describes the perspectives of patients and transplant professionals on ethical and logistical issues related to voucher donation. Strategies to address these issues as well to explore the perspectives of marginalized communities and of the general public are needed.</div></div>","PeriodicalId":17761,"journal":{"name":"Kidney International Reports","volume":"10 10","pages":"Pages 3494-3505"},"PeriodicalIF":5.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145242337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exome Sequencing in Saudi Arabian Pediatric Kidney Disease Single-Center Cohort","authors":"Katharina Lemberg ,&nbsp;Mohamed A. Shalaby ,&nbsp;Elena Zion ,&nbsp;Ken Saida ,&nbsp;Kirollos Yousef ,&nbsp;Ronen Schneider ,&nbsp;Nils D. Mertens ,&nbsp;Bshara Mansour ,&nbsp;Caroline M. Kolvenbach ,&nbsp;Lea M. Merz ,&nbsp;Korbinian M. Riedhammer ,&nbsp;Alina Braun ,&nbsp;Selina Hölzel ,&nbsp;Seyoung Yu ,&nbsp;Kraisoon Lomjansook ,&nbsp;Gina Kalkar ,&nbsp;Daniel Marchuk ,&nbsp;Izzeldin Elmubarak ,&nbsp;Gijs A.C. Franken ,&nbsp;Shirlee Shril ,&nbsp;Friedhelm Hildebrandt","doi":"10.1016/j.ekir.2025.07.011","DOIUrl":"10.1016/j.ekir.2025.07.011","url":null,"abstract":"<div><h3>Introduction</h3><div>In pediatric patients, monogenic causes are a significant contributor to kidney disease, ranging from approximately 10% in congenital anomalies of the kidney and urinary tract (CAKUT) to about 55% in renal ciliopathies. Exome sequencing has revealed numerous disease-causing genes and pathogenic variants. Nevertheless, continuous efforts are crucial to expand the knowledge base of these variants to establish unequivocal diagnoses. In this study, we report exome sequencing data from a single Saudi Arabian center, aiming to explore potential founder effects and determine specific genotype-phenotype correlations based on clinical diagnoses and genetic ancestry.</div></div><div><h3>Methods</h3><div>We consolidated 487 families with glomerular disease, CAKUT, cystic kidney disease, stone disease, and tubulopathies, recruited between 2007 and 2023 at King Abdulaziz University in Jeddah, Saudi Arabia. In these families, we performed exome sequencing and analyzed the data obtained for variants in established disease genes.</div></div><div><h3>Results</h3><div>In this highly consanguineous cohort (54%), 195 of 487 participants (40%) had glomerular disease, 160 of 487 (33%) had CAKUT, 44 of 487 (9%) had cystic kidney disease, 40 of 487 (8%) had stone disease, and 34 of 487 (7%) had tubulopathies. Pathogenic variants were identified in 45% of families with glomerular disease, 21% with CAKUT, 77% with cystic kidney disease, 58% with stone disease, and 76% of families with tubulopathy.</div></div><div><h3>Conclusion</h3><div>We identified a likely genetic cause of kidney disease in 43% of participants. Elucidating prevalent disease genes and disease variants in a defined region and genetic ancestry group provides important insights into variant pathogenicity assessment, disease management, and prognosis.</div></div>","PeriodicalId":17761,"journal":{"name":"Kidney International Reports","volume":"10 10","pages":"Pages 3564-3577"},"PeriodicalIF":5.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145242373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liquid Biopsy-Multiomics Link Adhesion Pathway Dysregulation to Kidney Injury Severity","authors":"Nanditha Anandakrishnan ,&nbsp;Zhengzi Yi ,&nbsp;Zeguo Sun ,&nbsp;Tong Liu ,&nbsp;Jonathan Haydak ,&nbsp;Sean Eddy ,&nbsp;Pushkala Jayaraman ,&nbsp;Stefanie DeFronzo ,&nbsp;Aparna Saha ,&nbsp;Qian Sun ,&nbsp;Dai Yang ,&nbsp;Anthony Mendoza ,&nbsp;Gohar Mosoyan ,&nbsp;Huei Hsun Wen ,&nbsp;Jia Fu ,&nbsp;Thomas Kehrer ,&nbsp;Rajasree Menon ,&nbsp;Edgar A. Otto ,&nbsp;Bradley Godfrey ,&nbsp;Joanna Yang ,&nbsp;Evren U. Azeloglu","doi":"10.1016/j.ekir.2025.07.021","DOIUrl":"10.1016/j.ekir.2025.07.021","url":null,"abstract":"<div><h3>Introduction</h3><div>Severe acute kidney injury (AKI) is strongly associated with the risk of developing chronic kidney disease; however, little is known about the cell type–specific mechanisms driving kidney injury severity.</div></div><div><h3>Methods</h3><div>In this multicenter observational study, we used clinically obtained liquid biopsy proteomics and machine learning (ML) to predict severe outcomes in patients with COVID-associated and non-COVID AKI. Further, we orthogonally combined 169 urine proteomics with 437 plasma proteomics samples and 40 urine sediment single-cell transcriptomics samples to identify complementary dysregulated mechanisms.</div></div><div><h3>Results</h3><div>Using a 10-fold cross-validated random forest algorithm, we identified a set of urinary proteins that demonstrate predictive power for both discovery and validation set with AUC of 87% and 76%, respectively. These predictive proteomics features obtained demonstrate that cell adhesion and autophagy-associated pathways are uniquely impacted in severe AKI. Differentially abundant proteins (DAPSs) associated with these pathways are highly expressed in cells of the juxtamedullary nephron, endothelial cells (ECs), and podocytes, indicating that these kidney cell types could be potential targets. Single-cell transcriptomic analysis in the <em>in vitro</em> model of kidney organoids infected with SARS-CoV-2 reveal dysregulation of extracellular matrix (ECM) organization in multiple nephron segments, recapitulating the clinically observed fibrotic response across multiomics datasets. Ligand-receptor interaction analysis of the podocyte and tubule organoid clusters shows significant reduction and loss of interaction between integrins and basement membrane receptors in the infected kidney organoids.</div></div><div><h3>Conclusion</h3><div>Collectively, these data suggest that ECM degradation and adhesion-associated mechanisms could be the main driver of severe kidney injury.</div></div>","PeriodicalId":17761,"journal":{"name":"Kidney International Reports","volume":"10 10","pages":"Pages 3592-3610"},"PeriodicalIF":5.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145242377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thrombotic Microangiopathy and Multiorgan Injury Following Chikungunya Vaccination","authors":"Jean-Michel Halimi ,&nbsp;Valentin Maisons ,&nbsp;Paul Delalande ,&nbsp;Christelle Barbet ,&nbsp;Bénédicte Sautenet ,&nbsp;Sophie Jacquier ,&nbsp;Justine Cibron ,&nbsp;Eric Piver ,&nbsp;Marie-Sara Agier","doi":"10.1016/j.ekir.2025.07.030","DOIUrl":"10.1016/j.ekir.2025.07.030","url":null,"abstract":"","PeriodicalId":17761,"journal":{"name":"Kidney International Reports","volume":"10 10","pages":"Pages 3701-3703"},"PeriodicalIF":5.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145242282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kidney Transplantation in Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis: Where do we Stand?","authors":"Pierre Pfirmann ,&nbsp;Hannah Kaminski","doi":"10.1016/j.ekir.2025.08.022","DOIUrl":"10.1016/j.ekir.2025.08.022","url":null,"abstract":"","PeriodicalId":17761,"journal":{"name":"Kidney International Reports","volume":"10 10","pages":"Pages 3300-3301"},"PeriodicalIF":5.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145242297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Busting a Myth: Sodium-Glucose Cotransporter-2 Inhibitors do not Cause Postoperative Acute Kidney Injury","authors":"Peter Rossing","doi":"10.1016/j.ekir.2025.08.034","DOIUrl":"10.1016/j.ekir.2025.08.034","url":null,"abstract":"","PeriodicalId":17761,"journal":{"name":"Kidney International Reports","volume":"10 10","pages":"Pages 3308-3310"},"PeriodicalIF":5.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145242298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Randomized Trial of Dapagliflozin in Patients With Nondiabetic Stage 4 CKD","authors":"Matias Trillini ,&nbsp;Alessandro Villa ,&nbsp;Annalisa Perna ,&nbsp;Tobia Peracchi ,&nbsp;Diego Fidone ,&nbsp;Nadia Rubis ,&nbsp;Chiara Guarinoni ,&nbsp;Davide Martinetti ,&nbsp;Annamaria Chiappa ,&nbsp;Tiziano Gamba ,&nbsp;Elena Perticucci ,&nbsp;Vincenzo Gambara ,&nbsp;Stefano Rota ,&nbsp;Nadia Stucchi ,&nbsp;Fabiola Carrara ,&nbsp;Giuseppe Remuzzi ,&nbsp;Piero Ruggenenti","doi":"10.1016/j.ekir.2025.07.020","DOIUrl":"10.1016/j.ekir.2025.07.020","url":null,"abstract":"<div><h3>Introduction</h3><div>Sodium-glucose cotransporter-2 (SGLT2) inhibitors are nephroprotective in patients with chronic kidney disease (CKD) and mild-to-moderate renal insufficiency.</div></div><div><h3>Methods</h3><div>This prospective, randomized, cross-over, placebo-controlled, double-blind study compared the effects of 6-week dapagliflozin (10 mg/d) with placebo treatment in 31 consenting nondiabetic Caucasian adults with stage 4 CKD and proteinuria &gt; 0.5 g/24 h. Participants were identified at the Nephrology Unit of Papa Giovanni XXIII Hospital and treated at Mario Negri Institute (Bergamo, Italy) between December 2021 and December 2023. Normalized glomerular filtration rate (GFR) (using iohexol plasma clearance) and 24-hour proteinuria (median of 3 urinary measurements) were co–primary outcomes. Analyses were by modified intention-to-treat.</div></div><div><h3>Results</h3><div>At 6 weeks, dapagliflozin significantly decreased GFR by 1.88 ± 5.00 ml/min per 1.73 m² (<em>P</em> = 0.022) and proteinuria by 0.50 (−0.10 to 0.80) g/24 h (<em>P</em> = 0.026) versus placebo. The dapagliflozin-induced GFR (<em>P</em> &lt; 0.001) and proteinuria (<em>P</em> = 0.003) reduction was already significant at 1 week. At 6 weeks, dapagliflozin reduced absolute GFR (<em>P</em> = 0.026), the CKD-Epidemiology Collaboration (CKD-Epi) equation–based estimated GFR (eGFR) (<em>P</em> = 0.003), the Modification of Diet in Renal Disease (MDRD) equation–based eGFR (<em>P</em> = 0.002), 24-hour albuminuria (<em>P</em> = 0.001), total protein (<em>P</em> = 0.057) and albumin (<em>P</em> = 0.009) fractional clearances, and fasting blood glucose (<em>P</em> &lt; 0.001); and increased serum albumin (<em>P</em> = 0.001), renin activity (<em>P</em> = 0.020), glucosuria (<em>P</em> &lt; 0.001), and glucose fractional clearance (<em>P</em> &lt; 0.001) versus placebo. All changes reversed completely after treatment withdrawal. GFR changes correlated inversely with changes in renal plasma flow (RPF) (<em>P</em> = 0.010) and positively with changes in postglomerular resistance (<em>P</em> &lt; 0.001) but did not correlate with changes in preglomerular resistance. There were no serious adverse events.</div></div><div><h3>Conclusion</h3><div>Dapagliflozin safely ameliorates (compensatory) glomerular hyperfiltration and proteinuria and is glycosuric in nondiabetic patients with preterminal CKD. GFR reduction is likely because of postglomerular vasodilation rather than preglomerular vasoconstriction.</div></div>","PeriodicalId":17761,"journal":{"name":"Kidney International Reports","volume":"10 10","pages":"Pages 3340-3355"},"PeriodicalIF":5.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145242229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of Calcineurin Inhibition in Children With Steroid-Resistant Nephrotic Syndrome","authors":"Agnes Trautmann ,&nbsp;Jonas Hofstetter ,&nbsp;Beata Lipska-Ziętkiewicz ,&nbsp;Alexey Tsygin ,&nbsp;Iwona Ogarek ,&nbsp;Bassam Saeed ,&nbsp;Maria Szczepanska ,&nbsp;Marta Azocar ,&nbsp;Francesco Emma ,&nbsp;Fatih Ozaltin ,&nbsp;Salim Caliskan ,&nbsp;Monica Bodria ,&nbsp;Dusan Paripovic ,&nbsp;Marcin Tkaczyk ,&nbsp;Jun Oh ,&nbsp;Mounia Boutaba ,&nbsp;Helena Jardim ,&nbsp;Alev Yilmaz ,&nbsp;Dagmar Csaicsich ,&nbsp;Bruno Ranchin ,&nbsp;Loai Akram Eid","doi":"10.1016/j.ekir.2025.07.037","DOIUrl":"10.1016/j.ekir.2025.07.037","url":null,"abstract":"<div><h3>Introduction</h3><div>We aimed to provide evidence for the efficacy of calcineurin inhibitor (CNI) treatment in children with steroid-resistant nephrotic syndrome (SRNS).</div></div><div><h3>Methods</h3><div>In 278 SRNS children receiving first-line CNI treatment, cumulative remission and kidney failure incidence were estimated using competing risk analysis. Kaplan-Meier and Cox regression analyses were performed to analyze kidney survival, identify predictors of CNI responsiveness and estimate the cumulative incidence of breakthrough proteinuria episodes on or off CNI treatment. The impact of CNI dosage and trough levels on proteinuria was assessed using multivariable linear-mixed effects modeling.</div></div><div><h3>Results</h3><div>Within 6 months of CNI administration, proteinuria was reduced by 84% (interquartile range: 80%–87%) in 219 nongenetic SRNS cases and by 58% (42%–70%) in 59 genetic SRNS cases but returned to pretreatment level in the latter group within 9 to 12 months. Whereas complete remission was observed in 91 of 219 nongenetic SRNS cases (42%) and 6 of 59 genetic SRNS cases (10%), remission was sustained in 53 nongenetic (24%) and 2 genetic (3%) cases only. Proteinuria reduction, but not attainment of complete remission, was associated with the use of higher CNI doses. The cumulative risk of breakthrough proteinuria on CNI treatment was 51% (40%–62%) and 65% (54%–75%) after 12 and 24 months, respectively, in nongenetic SRNS. The postdiscontinuation relapse risk in patients with complete remission was 40% (22%–59%) and 50% (30%–69%) after 12 and 24 months, respectively. Kidney survival in nongenetic SRNS was superior in CNI-responsive children (92% vs. 42% at 15 years), independent of breakthrough proteinuria episodes.</div></div><div><h3>Conclusion</h3><div>Our study provides real-world evidence regarding the extent, dynamics, dose-response relationship, and long-term functional impact of CNI therapy in nongenetic and genetic forms of SRNS.</div></div>","PeriodicalId":17761,"journal":{"name":"Kidney International Reports","volume":"10 10","pages":"Pages 3535-3548"},"PeriodicalIF":5.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145242371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidating Mechanisms of Hypomorphic WDR19-Related Kidney Failure","authors":"Omer Shlomovitz ,&nbsp;Yam Ben-Haim ,&nbsp;Netanel Eisenstein ,&nbsp;Leah Armon ,&nbsp;Igor Grinberg ,&nbsp;Sylvie Polak-Charcon ,&nbsp;Danit Atias-Varon ,&nbsp;Guy Chowers ,&nbsp;Dror Ben-Ruby ,&nbsp;Achia Urbach ,&nbsp;Asaf Vivante","doi":"10.1016/j.ekir.2025.07.019","DOIUrl":"10.1016/j.ekir.2025.07.019","url":null,"abstract":"<div><h3>Introduction</h3><div>Variants in the <em>WDR19</em> gene, a crucial component of the intraflagellar transport (IFT) complex A, are associated with renal-cystic ciliopathies, a prevalent cause of renal failure of genetic origin. In the Arab Druze population, a <em>WDR19</em> pathogenic missense variant (c.878G&gt;A; p.Cys293Tyr, termed <em>WDR19:C.878G&gt;A</em>) is the most common genetic cause of kidney failure manifesting as adult-onset, typically nonsyndromic chronic kidney disease (CKD). The underlying pathogenesis of this condition remains unclear.</div></div><div><h3>Methods</h3><div>We used CRISPR-Cas9 to induce patient-specific hypomorphic and loss-of-function (LoF) variants in human embryonic stem cells (hESCs), in addition to using patient-derived induced pluripotent stem cells (iPSCs) for differentiation into kidney organoids. Organoids were assessed by using immunofluorescence, electron microscopy, RNA-sequencing, and pathway analysis to elucidate the effects of these pathogenic variants on kidney development and ciliopathy characteristics.</div></div><div><h3>Results</h3><div>The <em>WDR19</em> hypomorphic variant impairs nephron development, causing delayed kidney organoid differentiation from early stages, cystogenesis, and structural abnormalities in both tubular and glomerular structures. Mutant organoids displayed reduced ciliation and shortened cilia. Both mutated organoids exhibited Sonic hedgehog dysregulation, where the pathway was upregulated in the presence of severe LoF variant and significantly reduced ciliation. Elevated sonic hedgehog (Shh) signaling was associated with significant downregulation of fibroblast growth factor (FGF) 8 (FGF8) and transcriptomic alterations in associated pathways, suggesting an inverse pathways relationship during kidney organoid development.</div></div><div><h3>Conclusion</h3><div>Our study validates the pathogenic role of the <em>WDR19</em> hypomorphic variant in adult-onset renal failure and highlights how hypomorphic pathogenic variants disrupt kidney development. These findings underscore the critical role of cilia in renal development, offering insight into the mechanisms of ciliopathies.</div></div>","PeriodicalId":17761,"journal":{"name":"Kidney International Reports","volume":"10 10","pages":"Pages 3578-3591"},"PeriodicalIF":5.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145242376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}