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We evaluated the in vitro effects of pH and Ca2+ concentration of peritoneal dialysis solution (PDS) on (1) the release of interleukin-1 (IL-1), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8) from peritoneal macrophages (PM0) and peritoneal mesothelial cells (PMC); (2) the release of IL-6 and IL-8 by PMC; and (3) the PM0 and PMC intracellular Ca2+ concentration. Aliquots of 5 X 106 PM0 and PMC were incubated (2 hr, 37° C) in 1 ml of physiologic growth medium (RPMI 1640) and in 1 ml of four different PDS (1.36 g/dl glucose): (1) type A PDS (pH 5.5, Ca2+ 1.75 mM), (2) type B PDS (pH 5.5, Ca2+ 1.25 mM), (3) type C PDS (bicarbonate buffered pH 7.4, Ca2+ 1.75 mmol/L, and (4) type D PDS (bicarbonate buffered pH 7.4, Ca2+ 1.25 mM); each was stimulated with S. epidermidis. Results showed that type A PDS samples induced an average 60% increase in PM0 and PMC cytoplasmic levels and in cytokine release, whereas with type B PDS samples there was a 90% decrease. Type C PDS samples did not modify the PM0 and PMC IL-6 and IL-8 production, whereas a 3-fold rise in the production of IL-1 and TNF-α by PM0 was seen; this was associated with an increase in PM0 and PMC Ca2+ cytoplasmic levels. When type D PDS samples were incubated, however, there was an average 40% decrease in PM0 and PMC cytoplasmic Ca2+ levels and in cytokine release. We conclude that bibarbonate buffered PDS in more biocompatible than conventional PDS having a 5.5 pH, because it maintains adequate concentrations of Ca2+ in the cytoplasm of PM0 and PMC and therefore adequate cytokine release. However, despite a neutral pH, low Ca2+ concentration in the PDS reduces PM0 and PMC cytoplasmic levels of Ca2+, thereby inhibiting cell activation.