Cytokine-induced peritoneal fibrosis in CAPD. Effects of Ca++ and 1,25(OH)2D3

We have demonstrated in some continuous ambulatory peritoneal dialysis (CAPD) patients with ultrafiltration (UF) loss, the role of increased peritoneal lymphocyte (PLy) and macrophage (PMO) Ca++ concentrations in the release of large amounts of gamma-interferon (gamma-IFN) and Interleukin-1 (IL-1), which stimulate peritoneal fibroblast proliferation. We have also shown in vitro and in vivo that the calcium channel blocker verapamil (VPM) is able to normalize the previously high PLy and PM0 Ca++ concentrations, and cytokine release; to decrease fibroblast proliferation; and to increase UF in 60% of the CAPD patients with UF loss due to a cytokine-mediated hyperproliferation of peritoneal fibroblasts, while in the remaining 40% there is little improvement (VPM responders and low-responders, respectively). To evaluate which mechanisms, in addition to passive Ca++ influx, can play a role in the Ca++-dependent activation of peritoneal immune cells, we evaluated the effects in vitro of different doses of Ca++ alone; with VPM; and with 1,25(OH)2D3 on: 1) PLy and PM0 cytoplasmic Ca++ levels; 2) gamma-IFN and IL-1 release by PLy and PM0; and 3) peritoneal fibroblast proliferation in six CAPD VPM low-responder patients. Results showed a direct correlation between Ca++ levels in the medium and PLy and PM0 Ca++ concentrations; IL-1 and gamma-IFN release; and peritoneal fibroblast proliferation. These effects were enhanced by the addition of low doses of 1,25(OH)2D3 to the medium, while both high 1,25(OH)2D3 doses and verapamil abrogated the Ca++-induced PLy and PM0 activation.(ABSTRACT TRUNCATED AT 250 WORDS)