Hyponatremia correction is associated with increased brain-derived neurotrophic factor levels: A pilot secondary analysis of a randomized, double-blind, placebo-controlled, crossover trial.

Chronic hyponatremia is associated with cognitive deficits, yet the underlying mechanisms remain elusive. A cerebral growth factor which is crucial for cognition and memory is brain-derived neurotrophic factor (BDNF), but its role in hyponatremia has never been investigated. We here examined the influence of hyponatremia correction on serum BDNF levels. This study represents a secondary post hoc analysis of a prospective randomized, double-blind, crossover, placebo-controlled trial. Nine patients with syndrome of inappropriate antidiuresis (SIAD) completed 4 weeks treatments with empagliflozin 25 mg/day versus placebo. Serum sodium, BDNF levels, and Montreal Cognitive Assessment (MoCA) were assessed at baseline and after treatment cycles. Median baseline sodium was 131 mmol/L [130-133], which increased to 134 mmol/L ([131-136], p = .04) after empagliflozin treatment and remained stable after placebo phase (130 mmol/L [126-132], p = .9). Sodium increase was significantly associated with BDNF increase, also after adjusting for treatment arm, sex, age, baseline sodium, and antidepressant treatment (per 1 mmol/L sodium increase: estimate = 0.70 ng/mL, p = .048). This association was stronger upon empagliflozin treatment as shown by the interaction analysis (p = .03). In a subgroup of patients reaching normonatremia after empagliflozin treatment, BDNF increase was slightly higher compared to patients with persistent hyponatremia. MoCA scores did not differ between empagliflozin and placebo phase. Sodium increase was significantly associated with an increase in neurocognitive biomarker BDNF. Further research is needed to clarify BDNF's role in cognitive impairment in hyponatremia and its response to different treatment approaches. Trial registration: ClinicalTrials.gov (NCT03202667).