Associations of Hyponatremia with Cognition Function and All-Cause Mortality: Post-Hoc Analysis of the Systolic Blood Pressure Intervention Trial

Background: Acute neurological effects of severe hyponatremia are well known. However, the long-term association of hyponatremia with cognitive impairment are unclear. Methods: In this post-hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), we examined whether incident hyponatremia is a risk factor for mild cognitive impairment (MCI) or probable dementia (PD). In those with baseline serum sodium ≥ 130 mmol/L, we defined incident hyponatremia in the first 6 months as a SPRINT safety alert for serum sodium < 130 mmol/L from randomization to the 6-month visit. In multivariate, Cox regression models adjusted for baseline cognitive function and other variables, we related incident hyponatremia in the first 6 months with subsequent MCI or PD in 8,540 participants with cognitive outcomes data and with all-cause mortality (ACM) in 9,135 participants with mortality data. Results: Incident hyponatremia in the first 6 months was noted in 116 (1.4%) participants. Older age, female sex, non-African American race, lower body mass index and randomization to intensive systolic blood pressure control were associated with incident hyponatremia. Compared to those without hyponatremia, those with incident hyponatremia had higher risk of PD (2.1 versus 0.9 events/ 100 person years, HR 3.08, 95% CI 1.48 to 6.41) but not MCI (3.1 versus 3.6 events/ 100 person years, HR 0.95, 95% CI 0.54 to 1.68) and the composite of MCI/ PD (5.0 versus 4.2 events/ 100 person years, HR 1.28, 95% CI 0.82 to 2.0). There were no significant differences in ACM (HR 1.84, 95% CI 0.90 to 3.73). Conclusions: Biological plausibility for the association of incident hyponatremia with PD but not MCI or death is unclear. The association of incident hyponatremia with PD could reflect a chance finding or non-causal biological association or causal relationship.