Urinary Albumin, Sodium, and Potassium and Cardiovascular Outcomes in the UK Biobank: Observational and Mendelian Randomization Analyses

Daniela Zanetti, Helene Bergman, Stephen Burgess, Themistocles L Assimes, Vivek Bhalla, Erik Ingelsson, Daniela Zanetti, Helene Bergman, Stephen Burgess, Themistocles L Assimes, Vivek Bhalla, Erik Ingelsson

Abstract

Urinary biomarkers are associated with cardiovascular disease, but the nature of these associations is not well understood. We performed multivariable-adjusted regression models to assess associations of random spot measurements of the urine sodium-potassium ratio (UNa/UK) and urine albumin adjusted for creatinine with cardiovascular risk factors, cardiovascular disease, and type 2 diabetes mellitus (T2D) in 478 311 participants of the UK Biobank. Further, we assessed the causal relationships of these kidney biomarkers, used as proxies for kidney function, with cardiovascular outcomes using the 2-sample Mendelian randomization approach. In observational analyses, UNa/UK showed significant inverse associations with atrial fibrillation, coronary artery disease, ischemic stroke, lipid-lowering medication, and T2D. In contrast, urine albumin adjusted for creatinine showed significant positive associations with atrial fibrillation, coronary artery disease, 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. After correcting for potential horizontal pleiotropy, we found evidence of causal associations of UNa/UK and albumin with BP (β systolic BP ≥2.63; β diastolic BP ≥0.85 SD increase in BP per SD change in UNa/UK and urine albumin adjusted for creatinine; P≤0.04), and of albumin with T2D (odds ratio=1.33 per SD change in albumin, P=0.02). Our comprehensive study of urinary biomarkers performed using state-of-the-art analyses of causality mirror and extend findings from randomized interventional trials which have established UNa/UK as a risk factor for hypertension. In addition, we detect a causal feedback loop between albumin and hypertension, and our finding of a bidirectional causal association between albumin and T2D reflects the well-known nephropathy in T2D.

Keywords: blood pressure; cardiovascular diseases; coronary artery disease; heart failure; type 2 diabetes mellitus.

Figures

Figure.
Figure.
Observational and Mendelian randomization (MR) analyses of urinary sodium-potassium ratio (UNa/UK) and urinary albumin-creatinine ratio (UAlb/UCr) with cardiovascular outcomes in UK Biobank. Binary outcomes: type 2 diabetes mellitus (T2D) and atrial fibrillation (AF). Continuous outcomes: systolic and diastolic blood pressure (SBP and DBP), body mass index (BMI), and waist-to-hip ratio (WHR). Main analysis (N=478 311) excluding participants with diagnoses indicating decreased kidney function (N=7221) and cardiovascular disease at baseline (N=17 087). Associations were performed using multivariable-adjusted linear, logistic, and Cox proportional hazards models in main observational analyses and inverse variance weighted method for MR. The betas from linear regression represent SD change in outcome variable per SD change in urinary sodium and potassium. The hazard and odds ratios are given per SD change in urinary sodium and potassium. Model adjustment: age, sex, region of the UK Biobank assessment center, ethnicity, smoking, alcohol, physical activity, Townsend index, blood pressure (DBP and SBP), obesity (BMI, body fat percentage, WHR), lipid medications, T2D, and medications affecting renal excretion. MR analyses performed using publicly available consortia data, except for blood pressure where we performed a genome-wide association studies (GWAS) in UK Biobank (as the publicly available GWAS summary statistics were adjusted for BMI). HR indicates hazard ratio; and OR, odds ratio.

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