Neurofilament Light Chain and Glial Fibrillary Acidic Protein as Potential Early Indicators of Osmotic Brain Stress in Hyponatremia and Its Correction

BACKGROUND: Hyponatremia is the most common electrolyte disorder. While overly rapid correction can cause osmotic demyelination syndrome (ODS), hyponatremia itself is linked to neurocognitive impairment. Despite this, the neurological burden remains underappreciated, and subclinical neuronal and astrocytic injury due to hyponatremia or its correction may be more frequent than recognized. Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are biomarkers of neuronal and astrocytic injury. OBJECTIVE: Whether hyponatremia and its treatment are associated with changes in serum NfL and GFAP levels. METHODS: Two randomized, double-blind, placebo-controlled trials. Study 1: healthy adults underwent experimentally induced hyponatremia within 8 hours. Study 2: hospitalized patients with hyponatremia were treated over 4 days. Biomarkers were measured at baseline and follow-up and analyzed as age- and BMI-adjusted Z-scores (for GFAP, also sex-adjusted). RESULTS: In healthy adults, blood sodium decreased by a median of 7 mmol/L [-8(-)-6] within 8 hours, associated with an increase in NfL (+0.48 Z-units [0.09-0.78]) and GFAP (+1.02 Z-units [0.84-1.39]). Patients with hyponatremia showed a baseline sodium of 126 mmol/L [122-127], which increased by 4 mmol/L [2-6] within 24 hours. NfL increased from a Z-score of 1.90 [1.06-2.51] by +0.21 [-0.03-0.66]; GFAP increased from 0.16 [-0.55-0.58] by +0.46 [0.12-0.81]. In multivariable models predicting biomarker Z-scores on day 5, both baseline biomarker levels and the degree of sodium increase within 24 hours were significant predictors. CONCLUSION: Hyponatremia and its correction are associated with measurable neuronal and astrocytic injury. NfL and GFAP may serve as early indicators of osmotic brain stress, suggesting ODS may represent only the visible part of a broader spectrum of cerebral vulnerability.