ZINC MODULATES MONONUCLEAR CELLULAR CALCITRIOL METABOLISM IN PERITONEAL-DIALYSIS PATIENTS

Zinc has long been known to play a role in maintaining immunologic fun ction. Hypozincemia, however, is common in patients with end-stage ren al disease (ESRD) treated with continuous ambulatory peritoneal dialys is (CAPD). We previously demonstrated that zinc depletion limits the a bility of animals to achieve maximum circulating calcitriol levels in response to the stress of calcium or phosphorus depletion. It was uncl ear, however, whether changes in the circulating levels of calcitriol in these settings was associated with a direct effect on renal 1-alpha hydroxylase activity, or whether the zinc dependence of the stimulate d calcitriol response involved an integrated systemic response in inta ct animals. In addition it was unclear whether circulating zinc levels or zinc nutritional status modified calcitriol metabolism in humans. To better understand the role zinc plays in the immune response in pat ients with ESRD, we studied IL-1, calcitriol and tumor necrosis factor -alpha production by mononuclear cells from blood and peritoneal efflu ents of 22 patients with ESRD treated with CAPD. Macrophages from peri toneal effluents and peripheral blood mononuclear cells were isolated and pulsed with phytohemagglutinin in medium to which different concen trations of zinc chloride, copper chloride, and carbonyl cyanide p-(tr ifluoromethoxy)-phenyl-hydrazone (FCCP), an inhibitor of mitochondrial function were added. Supernatant interleukin-l, calcitriol, and tumor necrosis factor-alpha levels were subsequently measured. We demonstra ted a zinc concentration dependent increase in stimulated IL-1 alpha a nd -beta, and TNF-alpha release in both peripheral mononuclear cells a nd peritoneal macrophages from patients with ESRD treated with CAPD. T he effect is zinc specific, as it is not reproduced by copper or chlor ide supplementation. A zinc concentration dependent increase in perito neal macrophage calcitriol release was also noted. FCCP blocked the ce llular production of IL-1 alpha, IL-1 beta, and TNF-alpha, but had lit tle effect on zinc-induced stimulated mononuclear cell supernatant cal citriol levels. The different shape of the zinc dose response curve, a nd the lack of correlation between paired IL-1 and calcitriol supernat ant levels suggests the effect of zinc on mononuclear cellular cytokin e and calcitriol production is mediated through different pathways.