A recent article by Shin Ahn and colleagues in Journal of the American Geriatrics Society reports data from a longitudinal study that shows a strong association between low-normal serum sodium and mortality (1). While prior studies from multiple countries have shown a relationship between abnormally low sodium values and mortality (2-4), this is the first report to show a strong relationship between sodium levels in the normal range (135–145 mEq/L) and risk of death.
The data are from the Korean Longitudinal Study on Aging, which enrolled 1000 randomly selected community-based elders in 2005. Survival status was determined over 63.3 ± 16.6 months of follow-up. Subjects were stratified into 3 groups according to baseline serum sodium values (corrected for serum glucose levels): Group 1 (sodium 135.0–138.0 mEq/L, 7.7% of population), Group 2 (sodium 138.1–142.0, 66.9%), Group 3 (sodium 142.1–145.0, 25.4%). Group 1 subjects were 2.7 times more likely to die during follow-up than subjects in group 2. The 5-year survival rate was 61.6% in group 1, 83.5% in group 2, and 80.9% in group 3 (P < .001).
To attempt to compensate for potential confounding co-morbidities, the groups were further stratified according to various conditions related to serum sodium concentration of 138.0 or less (such as sex, age, diabetes, hypertension, thyroid function, diuretics, anemia, and proteinuria), and the relationship between sodium and mortality remained. The excess deaths related to low sodium were predominately cardiovascular. The authors also showed that correcting serum sodium for glucose levels, which is not typically done when looking at electrolyte values, tended to sharpen the relationship between sodium level and mortality.
These results are intriguing because clinicians have long assumed that laboratory values in the normal range are in fact “normal” and not particularly predictive of poor outcomes. We may need to rethink this assumption. With regard to blood pressure, we know that “low normal” is generally better than “high normal,” but this is not generally the case with most lab values (although in thinking this through we might want to study this for other values, such as hemoglobin, albumin, or thyroid levels). In trying to explain why low-normal sodium might be predictive of mortality, the authors consider several possibilities, including higher CRP levels in the low-normal sodium group, as well as higher rates of anemia and proteinuria. However, they were not able to verify any of these theories.
Of course, this is only one study, and results need to be verified in other populations. Moreover, these data only show an association, and causation is far from demonstrated. Nonetheless, it will be important to consider the possible relationship between laboratory values within normal ranges and clinical outcomes.
1. Ahn SY, Park YS, Lee SW, et al. Association between small decrease in serum sodium concentration within the normal range and all-cause and cardiovascular mortality in elderly adults over 5 years. J Am Geriatr Soc 64:510-7, 2016.
2. Gankam-Kengne F, Ayers C, Khera A, et al. Mild hyponatremia is associated with an increased risk of death in an ambulatory setting. Kidney Int 83:700-6, 2013.
3. Mohan S, Gu S, Parikh A, et al. Prevalence of hyponatremia and association with mortality: Results from NHANES. Am J Med 126:1127–1137, 2013.
4. Sajadieh A, Binici Z, Mouridsen MR, et al. Mild hyponatremia carries a poor prognosis in community subjects. Am J Med 122:679–686, 2009.