In this study, we present a new protocol for kidney replacement therapy (hemodialysis), based on an explicitly solvable mathematical model. With current protocols, the high and constant level of bath bicarbonate (HCO<sub>3</sub><sup>−</sup>) used to prevent metabolic acidosis leads to very rapid delivery of HCO<sub>3</sub><sup>−</sup> into the patient during the first part of the therapy. This rapid alkalinization elicits a robust buffer response that, paradoxically, consumes more HCO<sub>3</sub><sup>−</sup> than is added during the remainder of the treatment. In previous studies, we developed an analytical model that allows one to quantify these events and tested alternative protocols manipulating the rate of rise in blood bicarbonate concentration (HCO<sub>3</sub><sup>−</sup>). The protocol tested in this paper enforces a more gradual increase in blood HCO<sub>3</sub><sup>−</sup>, by means of a model-based staircase adjustment of bath HCO<sub>3</sub><sup>−</sup>. Model equations predict a reduction of buffer response and rate of organic acid production. These predictions are tested in 20 stable outpatients receiving hemodialysis. We find that the proposed protocol achieves the desired profile of blood HCO<sub>3</sub><sup>−</sup> with good accuracy and reduces the total buffer response by 1/3 and the rate of lactic acid production by at least 1/4, as compared to conventional therapy. Although more studies are needed, we believe that our work will pave the way for a more rational approach to correction of acidosis during hemodialysis. Article Highlights <list list-type="bullet"><list-item><label>•</label> Our study tests an analytic model designed to enforce a more gradual rate of bicarbonate delivery during hemodialysis. </list-item><list-item><label>•</label> Using our model, we show that we can reduce the excessive buffer response and lactic acid production that occur with the conventional approach. </list-item><list-item><label>•</label> We demonstrate that our model can provide a rational approach to bicarbonate addition during treatment. </list-item> </list>