Objective Using the erythrocyte as a model for other kinds of cells not directly exposed to peritoneal dialysis (PD) solutions, we investigated the tolerance of the cell metabolism to lactate and bicarbonate buffers Design We studied, in vivo (in two groups of 5 PD patients each) and in vitro, the Embden-Meyerh of pathway (EMP) because it represents a potential target for the unphysiological effects of lactate or bicarbonate buffers. The EMP is the main glucose-utilizing route in the red blood cell (RBC), producing energy and reducing power. Methods The enzymatic activities of the key steps in the glycolytic pathway and the energy charge (EC), determined by the levels of phosphorylated adenine nucleotides, were investigated spectrophotometrically and by high performance liquid chromatography (HPLC) in two groups of patients undergoing lactate (L-group) and bicarbonate (B-group) PD, respectively. The in vitro effects of both bicarbonate and lactate buffers on some EMP enzyme activities and energy production were determined. Cellular pH (pHi) was also investigated. Results The B-group showed an EC value near the control levels, while in the L-group a significantly lower EC value was observed (t-test: p < 0.05 vs both B-group and controls). The key enzymes in the EMP, and in particular hexokinase, were higher in the L versus B-group (p < 0.03 for the comparison of the Hk mean values). As demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, the bound form of glyceraldehyde-3-phosphate dehydrogenase (G-3-PD), an inactive form of this EMP enzyme, was significantly higher in the Lgroup with respect to the B-group (p< 0.004). In thein vitro experiments, high lactate concentrations acutely inhibited the key enzymatic steps of glycolysis, producing a significant decrease in glucose consumption and adenosine triphosphate production. These effects were not observed when bicarbonate was used in the incubations. Bothin vivoandin vitrolactate, but not bicarbonate, induce a significant drop in pHi (p < 0.05). Decreased levels of pHi like those observed in the lactate-incubated RBC were demonstrated to be able to inhibit G-3-PD activity (25±2%) here used as an indicator of the actual decrease in pH. Conclusion This study provides evidence for a damaging action of lactate with respect to bicarbonate buffer on the RBC metabolism. This condition was demonstrated observing a cell energy depletion, which coincidesin vitro with an acute EMP impairment; the lactate accumulation together with the consequent lowering of pHi seem to be responsible for this effect, which was not observed when bicarbonate was used instead of lactate.