Formulas to estimate dietary sodium intake from spot urine lead to misleading associations with cardiovascular disease risk and mortality

Objectives: To test the hypothesis that the association of formula-estimated sodium intake from spot urine with cardiovascular disease is independent of spot urinary sodium concentration.

Methods: We included 435 336 participants in the UK Biobank whose sodium intake was estimated from spot urine using INTERSALT, Kawasaki, and Tanaka formulas. Hazard ratios for cardiovascular disease (CVD) events and deaths were estimated using Cox proportional-hazard model adjusted for multiple covariates. Penalized Cox regression was used to assess nonlinear relations. Hazard ratios were recalculated after replacement of the sodium concentration term with sex-specific mean values (women: 67.5 mmol/l; men: 89.8 mmol/l) to assess how other components of the formulas influenced these associations.

Results: Forty-four thousand two hundred and sixty-eight CVD events and 3251 CVD deaths occurred during a median follow-up of 12 years. The mean estimated sodium intake was 143 (SD = 35), 178 (52), and 147 (33) mmol/day based on INTERSALT, Kawasaki, and Tanaka formulas, respectively. For CVD incidence, linear inverse associations were observed for INTERSALT and Tanaka estimates [hazard ratios (95% CIs) for every 50 mmol reduction in estimated sodium intake: 0.9 (0.83-0.97) and 0.93 (0.89- 0.97); P-linear = 0.0047 and 0.0021], and a U-shaped association for the Kawasaki estimates (P-nonlinear = 0.0026). When the sodium concentration term was fixed, inverse associations were seen for all formulas [0.86 (0.77-0.95), 0.96 (0.93-0.99) and 0.94 (0.89-0.99) for INTERSALT, Kawasaki, and Tanaka; P linear = 0.0054, 0.0166 and 0.0188]. For CVD mortality, no association was observed, but a nonlinear association was identified for the INTERSALT equation (P-nonlinear = 0.0287) after fixing the sodium concentration.

Conclusion: These formula-estimated sodium intakes were associated with CVD incidence and mortality independently of spot urinary sodium concentration. We recommend these formulas not be used in studies associating sodium intake with CVD outcomes to avoid generating misleading evidence.