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Cardiovascular disease is the leading cause of mortality in hemodialysis patients. A chronic state of volume and pressure overload contributes, and central to this is the net sodium balance over the course of a hemodialysis. Of recent interest is the contribution of the dialysate sodium concentration (Dial-Na+) to clinical outcomes. Abundant evidence confirms that in thrice-weekly conventional hemodialysis, higher Dial-Na+ associates with increased intradialytic weight gain, blood pressure, and cardiovascular morbidity and mortality. On the other hand, low Dial-Na+ associates with intradialytic hypotension in the same patient population. However, the effect of Dial-Na+ in short hours daily hemodialysis (SHD; often referred to as “quotidian” dialysis), or nocturnal dialysis (FHND) is less well studied. Increased frequency and duration of exposure to a diffusive sodium gradient modulate the way in which DPNa+ alters interdialytic weight gain, predialysis blood pressure, and intradialytic change in blood pressure. Furthermore, increased dialysis frequency appears to decrease the predialysis plasma sodium setpoint (SP), which is considered stable in conventional thrice-weekly patients. This review discusses criteria to determine optimal Dial-Na+ in conventional, SHD and FHND patients, and identifies areas for future research.