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BACKGROUND/OBJECTIVES: Hyponatremia is a risk factor for mortality in hemodialysis (HD) patients. It is not well known to which extent the comorbidities, malnutrition, fluid status imbalance and inflammation are related to hyponatremia and affect outcomes. SUBJECTS/METHODS: We studied 8883 patients from the European subset of the international MONitoring Dialysis Outcomes initiative. Nutritional and fluid statuses were assessed by bioimpedance spectroscopy. Fluid depletion was defined as overhydration ≤ -1.1 l and fluid overload as overhydration >+1.1 l, respectively. Malnutrition was defined as a lean tissue index below the 10th percentile of age- and gender-matched healthy controls. Hyponatremia and inflammation were defined as serum sodium levels < 135 mEq/l and C-reactive protein levels >6.0 mg/l, respectively. We used logistic regression to test for predictors of hyponatremia and Cox proportional hazards analysis to assess the association with all-cause mortality. RESULTS: Hyponatremia was predicted by the presence of malnutrition (odds ratio (OR) = 1.49 (95% confidence interval (CI) = 1.30-1.70), inflammation (OR= 1.44 (95% CI = 1.26-1.64)) and fluid overload ((> +1.1 l to +2.5 l) OR = 0.73 (95% CI = 0.62-0.85)) but not by fluid depletion (OR =1.34 (95% CI = 0.92-1.96)). Malnutrition, inflammation, fluid overload, fluid depletion and hyponatremia (hazard ratio =1.70 (95% CI = 1.46-1.99)) were independent predictors for all-cause mortality. CONCLUSIONS: In HD patients, hyponatremia is associated with malnutrition, inflammation and fluid overload. Hyponatremia maintained predictive for all-cause mortality after adjustment for malnutrition, inflammation and fluid status abnormalities. The presence of hyponatremia may assist in identifying HD patients at increased risk of death. European Journal of Clinical Nutrition (2016) 70, 779-784; doi: 10.1038/ejcn.2016.49; published online 20 April 2016, INTRODUCTION Hyponatremia has recently emerged as a risk factor for mortality in chronic hemodialysis (HD) patients. (1-3) The association between hyponatremia and mortality is not limited to HD patients but [...]