Uromodulin as a genetically anchored biomarker stratifies time to valve intervention in aortic regurgitation

Background 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. Methods We investigated renal biomarkers in individuals with AR from the UK Biobank ( n = 2,493) 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. Results 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 0.34–0.98; p = 0.041), whereas conventional renal markers (creatinine, urea, microalbumin) showed no association. UMOD levels were strongly associated with lower arterial stiffness ( β = −5.32 ± 0.27; p < 0.001 and lower systolic blood pressure ( β = −0.91 ± 0.13; p < 0.001), 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. Conclusions 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–AR 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.