Kidney Tubular Secretion Capacity and Risk of Cardiovascular Mortality in the General Population

BACKGROUND: Kidney tubular secretion is a critical mechanism for the clearance of numerous metabolites, toxins, and drugs. In populations with advanced chronic kidney disease (CKD), low (worse) tubular secretion has been associated with an increased risk of cardiovascular disease (CVD). However, it remains unknown whether this relationship is also present in the general population. METHODS: In this case-cohort study, we selected a 10% random subcohort (n=1246) from Trøndelag Health Study (HUNT-3, a Norwegian community-dwelling population cohort) and we also sampled 141 CVD death cases that occurred outside of the subcohort. We developed a summary secretion score by averaging urine-to-plasma ratios of twelve endogenous secreted solutes, with lower ratios indicating worse tubular secretion. Weighted Cox proportional hazards models were used to assess the relationship between the summary secretion score and the risk of CVD mortality. RESULTS: The mean (SD) age was 51 (14) years, 54.4% were females, 6% had prevalent CVD, and median (IQR) eGFR was 99 (90-110) mL/min/1.73m2 at baseline. In multivariable models adjusted for demographics, CVD risk factors, eGFR, and albuminuria, each SD lower summary secretion score was associated with 27% higher risk of CVD mortality (95% CI 1.03, 1.56). Results were similar across major demographic categories and among those with or without eGFR <60 ml/min/1.73 m2 or albuminuria >30 mg/g at baseline. CONCLUSIONS: Among community-dwelling participants, lower tubular secretion was associated with increased CVD mortality independent of eGFR, albuminuria, and other CKD risk factors.