Urinary Metals, Soluble Urokinase Plasminogen Activator Receptor, and Outcomes in the Multi‐Ethnic Study of Atherosclerosis

BACKGROUND: Environmental metal exposure is associated with cardiovascular disease (CVD) and mortality, potentially through inflammation. Soluble urokinase plasminogen activator receptor (suPAR), a stable marker of immune activation associated with CVD and death, may capture this pathway. We examined associations of urinary metals with suPAR and whether suPAR-associated components were present in cadmium-outcome associations. METHODS: In the Multi-Ethnic Study of Atherosclerosis, we studied 5,148 adults free of clinical CVD (2000-2002). We estimated associations of 11 creatinine-standardized urinary metals with serum suPAR by linear regression (per interquartile-range [IQR] increase), compared associations across suPAR, high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and D-dimer, and used VanderWeele 4-way decomposition to estimate suPAR-associated indirect components of cadmium associations with all-cause mortality and four adjudicated cardiovascular outcomes. RESULTS: Of 11 metals, 7 were associated with suPAR; cadmium showed the strongest association (7.99% higher suPAR per IQR; 95% CI, 6.14-9.87) followed by cobalt, copper, molybdenum, tungsten, and zinc, whereas barium was inversely associated. The association was monotonic and persisted among never-smokers (5.54%; 95% CI, 3.03-8.11). Over a median 14.7 years, higher urinary cadmium was associated with all-cause mortality (Q4-vs-Q1 hazard ratio, 1.43; 95% CI, 1.18-1.74); the suPAR-associated proportion was 0.30 (95% CI, 0.13-0.47). CONCLUSIONS: Cadmium showed a larger association with suPAR than with hs-CRP, IL-6, or D-dimer. An exploratory decomposition identified a suPAR-associated component of this association. Findings for cardiovascular outcomes were directionally consistent but not definitive. suPAR-related immune activation is a candidate pathway linking cadmium to mortality, warranting longitudinal and mechanistic confirmation.