Association between albuminuria, incident cardiovascular events, and mortality in persons without hypertension, diabetes, and cardiovascular disease.

Epidemiological studies have reported associations between elevated urine levels of albumin (albuminuria) and risk of cardiovascular (CV) events. A meta-analysis showed that albuminuria could improve CV risk prediction beyond established risk factors, and albuminuria was recently suggested as a surrogate endpoint for the progression of kidney disease. In current clinical practice, albuminuria screening is predominantly performed in the staging of kidney disease or in persons with hypertension or diabetes as a marker for end-target organ damage. It remains unclear if albuminuria screening for CV risk assessment should be extended to persons without diabetes and hypertension. Our aim was to investigate the association between albuminuria and 10-year risk of a composite CV outcome in adults without hypertension or diabetes in the UK Biobank study. Among participants with urinary biomarker data (n = 483 993), we excluded those who had withdrawn consent, an outcome event before baseline, and prevalent hypertension, diabetes, or a history of CV disease. Our study was approved by the UK Biobank (project 42176) and the Swedish Ethical Review Authority (Dnr.: 201902328). The composite CV outcome combined the first event of CV death, acute myocardial infarction, stroke, or heart failure. We calculated the urine albumin-to-creatinine ratio (ACR) and Cox regression was used with censoring at the first event, death, or the last date of follow-up (31 March 2017). Analyses were adjusted for CV risk factors: age, sex, ethnicity, smoking, systolic and diastolic blood pressure, total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, aspirin, lipid-lowering medication, glycosylated haemoglobin type A1c (HbA1c), body mass index, and creatinine-estimated glomerular filtration rate (eGFR). Missing values were imputed by predictive mean matching. In secondary analyses, we compared the following risk subgroups: current vs. non-smokers, ever vs. never smokers, impaired vs. normal kidney function (eGFR > 60 mL/min/1.73 m), presence vs. absence of dyslipidaemia (lipid-lowering treatment), triglycerides >_2. 0 mmol/L or LDL-C >_4. 1 mmol/L, high-normal vs. normal blood pressure (>120/ 80 mmHg), and HbA1c in the pre-diabetic vs. normal rage (>_39 mmol/mol). We compared the predictive performance of albuminuria with that of eGFR with regard to risk discrimination (Harrell’s C), explained variance, and model fit (likelihood ratio test). We included 198 637 persons aged 54± 8 years (62.7% women) without hypertension, diabetes, or CV disease at baseline (a flowchart is provided as Supplementary material online, Figure S1). Sample characteristics are shown in Table 1 and incidence rates for outcomes during up to 10 years’ follow-up (mean 7.1, median 7.0, range 5.4– 10.0 years) are displayed in Supplementary material online, Table S1. More than 5% of participants had prevalent microalbuminuria or macroalbuminuria (5.6% and 0.1%, respectively). Raised urine ACR was associated with increased 10-year risk of the composite CV outcome following adjustment for CV risk factors [hazard ratio (HR) per log unit in ACR, 1.21, 95% confidence interval 1.14–1.29, P = 9.0 10] (Figure 1A and Supplementary material online, Table S1). The increase in risk was more evident in ACR levels above the microalbuminuria threshold (Figure 1B). Similar associations were observed for CV mortality, all-cause mortality and the individual outcomes myocardial infarction, stroke, and heart failure. A heatmap (Supplementary material online, Figure S2) of HRs for albuminuria in combination with dyslipidaemia and smoking indicates ACR as an independent risk factor in addition to established risk markers. In the comparison between subgroups (Figure 1C and Supplementary material online, Table S2), raised ACR was strongly associated with increased CV risk, regardless of smoking, kidney function, dyslipidaemia, blood pressure, or pre-diabetes. To compare ACR to eGFR as an alternative marker of kidney function, we assessed both as added components of the ACC/AHA’s Atherosclerotic CV Disease (ASCVD) model, and the ESC’s Systematic Coronary Risk Evaluation (SCORE) model for 10-year CV risk and CV mortality risk, respectively (Supplementary material online, Table S3). For the composite