{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T06:12:24Z","timestamp":1778739144853,"version":"3.51.4"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"\n Background<\/jats:title>\n Aortic regurgitation (AR) frequently remains asymptomatic for prolonged periods, with guideline recommendations for intervention largely guided by imaging-based assessment of left ventricular remodeling. While renal dysfunction has been linked to adverse outcomes in AR, prior studies have predominantly focused on advanced disease stages and post-interventional outcomes, with limited data on pre-interventional progression, offering limited insight into pre-interventional disease progression or biologically informed approaches to risk stratification.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We investigated renal biomarkers in individuals with AR from the UK Biobank (\n n<\/jats:italic>\n \u2009=\u20092,493) and assessed associations with time to aortic valve replacement (AVR) using Cox proportional hazards models. Associations with cardiovascular imaging and hemodynamic phenotypes were examined via logistic regression. To place clinical findings in a biological context, we performed genome-wide colocalization analyses between AR phenotypes, blood pressure, and renal traits, followed by regulatory annotation, single-cell RNA sequencing (Kidney Cell Atlas), and phenome-wide association analyses.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Among patients with AR, higher circulating UMOD levels were independently associated with a lower risk of subsequent AVR (adjusted HR per SD 0.57, 95% CI 0.34\u20130.98;\n p<\/jats:italic>\n \u2009=\u20090.041), whereas conventional renal markers (creatinine, urea, microalbumin) showed no association. UMOD levels were strongly associated with lower arterial stiffness (\n \u03b2<\/jats:italic>\n \u2009=\u2009\u22125.32\u2009\u00b1\u20090.27;\n p<\/jats:italic>\n \u2009&lt;\u20090.001 and lower systolic blood pressure (\n \u03b2<\/jats:italic>\n \u2009=\u2009\u22120.91\u2009\u00b1\u20090.13;\n p<\/jats:italic>\n \u2009&lt;\u20090.001), both associated with disease progression, but not with left ventricular volumes. Genome-wide colocalization identified a shared genetic signal at the UMOD locus linking AR, blood pressure, and kidney function. Regulatory annotation and single-cell data localized UMOD expression to the thick ascending limb of Henle's loop, supporting a tubular-specific mechanism. Phenome-wide analyses further implicated UMOD variants in renal tubular and hemodynamic traits.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n These findings identify uromodulin as a genetically anchored, kidney-specific biomarker associated with pre-interventional progression and timing of valve intervention in AR. Our study shifts the renal\u2013AR paradigm from post-operative risk modification toward a mechanistically grounded model of tubular-driven disease progression, with implications for earlier risk stratification and surgical referral.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fcvm.2026.1839906","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T05:33:35Z","timestamp":1778736815000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Uromodulin as a genetically anchored biomarker stratifies time to valve intervention in aortic regurgitation"],"prefix":"10.3389","volume":"13","author":[{"given":"Emily","family":"Ghanbari","sequence":"first","affiliation":[{"name":"Department of Cardiology, Angiology and Intensive Care, German Heart Center of Charit\u00e9, Campus Benjamin Franklin","place":["Berlin, Germany"]},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin","place":["Berlin, Germany"]},{"name":"Institute of Active Polymers and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Hereon","place":["Teltow, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anastasiia","family":"Diagel","sequence":"additional","affiliation":[{"name":"Department of Cardiology, German Heart Center Munich, Technical University Munich","place":["Munich, Germany"]},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Munich","place":["Munich, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth","family":"Str\u00e4ssler","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Intensive Care, German Heart Center of Charit\u00e9, Campus Benjamin Franklin","place":["Berlin, Germany"]},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin","place":["Berlin, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Sannino","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Intensive Care, German Heart Center of Charit\u00e9, Campus Benjamin Franklin","place":["Berlin, Germany"]},{"name":"Friede Springer Cardiovascular Prevention Center at Charit\u00e9","place":["Berlin, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolle","family":"Kr\u00e4nkel","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Intensive Care, German Heart Center of Charit\u00e9, Campus Benjamin Franklin","place":["Berlin, Germany"]},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin","place":["Berlin, Germany"]},{"name":"Friede Springer Cardiovascular Prevention Center at Charit\u00e9","place":["Berlin, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus","family":"Reinthaler","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Intensive Care, German Heart Center of Charit\u00e9, Campus Benjamin Franklin","place":["Berlin, Germany"]},{"name":"Institute of Active Polymers and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Hereon","place":["Teltow, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulf","family":"Landmesser","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Intensive Care, German Heart Center of Charit\u00e9, Campus Benjamin Franklin","place":["Berlin, Germany"]},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin","place":["Berlin, Germany"]},{"name":"Friede Springer Cardiovascular Prevention Center at Charit\u00e9","place":["Berlin, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ursula","family":"Rauch-Kr\u00f6hnert","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Intensive Care, German Heart Center of Charit\u00e9, Campus Benjamin Franklin","place":["Berlin, Germany"]},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin","place":["Berlin, Germany"]},{"name":"Institute of Active Polymers and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Hereon","place":["Teltow, Germany"]},{"name":"Friede Springer Cardiovascular Prevention Center at Charit\u00e9","place":["Berlin, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhifen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, German Heart Center Munich, Technical University Munich","place":["Munich, Germany"]},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site 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