Background: Urinary biomarkers are associated with hypertension and cardiovascular disease (CVD), but the nature of these associations is incompletely understood. Methods: We performed multivariable-adjusted regression models to assess associations of urinary sodium-potassium ratio (UNa/UK), and urinary albumin adjusted for creatinine (UAlb/UCr) with cardiovascular risk factors, CVD and type 2 diabetes (T2D) in 478,311 participants of the UK Biobank. Further, we studied above associations separately in men and women, and assessed the causal relationships of these kidney biomarkers with cardiovascular outcomes using the two-sample Mendelian randomization (MR) approach. Results: In observational analyses, UNa/UK showed significant inverse associations with atrial fibrillation (AF), coronary artery disease (CAD), ischemic stroke, lipid-lowering medication and T2D. In contrast, UAlb/UCr showed significant positive associations with AF, CAD, heart failure, hemorrhagic stroke, lipid-lowering medication and T2D. We found a positive association between UNa/UK and albumin with blood pressure (BP), as well as with adiposity-related measures. Generally, we detected consistent directionality in sex-stratified analyses, with some evidence for sex differences in the associations of urinary biomarkers with T2D and obesity. After correcting for potential horizontal pleiotropy, we found evidence of causal associations of UNa/UK and albumin with systolic BP (betaSBP≥2.63; betaDBP≥0.85 SD increase in systolic BP per SD change UNa/UK and UAlb/UCr; P≤0.038), and of albumin with T2D (odds ratio=1.33 per SD change in albumin, P=0.023). Conclusion: Our Mendelian randomization analyses mirror and extend findings from randomized interventional trials which have established sodium intake as a risk factor for hypertension. In addition, we detect a feed-back causal loop between albumin and hypertension, and our finding of a bidirectional causal association between albumin and T2D reflects the well-known nephropathy in T2D.

Urinary biomarkers and cardiovascular outcomes in the UK Biobank: observational and Mendelian randomization analyses