Dialysis patients have increased susceptibility to infection and this is, in part, due to impaired phagocytic and bactericidal activities of polymorphonuclear leukocytes (PMNL). The mechanisms responsible for the reduced phagocytosis are not known. Dialysis patients have elevated blood levels of parathyroid hormone (PTH), and available data indicate that PMNL is a target cell for PTH. Chronic exposure to excess PTH may cause accumulation of calcium in PMNL which in turn could adversely affect cellular events leading to their dysfunction. We studied phagocytosis, resting levels of cytosolic calcium ([Ca²⁺]_i), ATP content and the rise in [Ca²⁺]_i in response to ligation of Fcγ RIII receptors with 3G8 monoclonal antibody in PMNL from 37 dialysis patients and 48 normal subjects. The PMNL from the dialysis patients displayed impaired phagocytosis, elevated resting levels of [Ca²⁺]_i, decreased ATP content and a smaller rise in [Ca²⁺]_i in response to various doses of 3G8 monoclonal antibody as compared to values obtained in PMNL of normal subjects. Our results suggest that derangements in cellular metabolism and possibly an abnormality in Fcγ RIII interaction with antibody and/or the consequences of such interaction are responsible, at least in part, for the impaired phagocytosis of PMNL of dialysis patients. Our data are consistent with the notion that excess PTH may play an important role in the processes leading to impaired phagocytosis.

It has been suggested that a sustained rise in resting levels of cytosolic calcium jCa2+Ji of pancreatic islets is responsible for impaired insulin secretion in chronic renal failure (CRF). Evidence for such an event is lacking and the mechanisms through which it may affect insulin secretion are not known. Studies were conducted in normal, CRF, and normocalcemic, parathyroidectomized (PTX) CRF rats to answer these questions.Resting levels of [Ca2+J1 of islets from CRF rats were higher (P < 0.01) than in control or CRF-PTX rats. [3HJ2-deoxyglucose uptake and cAMP production by islets were not different in the three groups. Insulin content of, and glucose-induced insulin secretion by islets from CRF rats was lower (P < 0.01) than in control and CRF-PTX rats. In contrast, glyceraldehydeinduced insulin release by CRF islets was normal. Basal ATP content, both glucose-stimulated ATP content and ATP/ADP ratio, net lactic acid output, V,, of phosphofructokinase-1, and Ca2"ATPase of islets from CRF rats were lower (P < 0.02-<0.01) than in normal or CRF-PTX animals.Data show that: (a) Glucose but not glyceraldehyde-induced insulin secretion is impaired in CRF; (b) the impairment in glucose-induced insulin release in CRF is due to a defect in the metabolism of glucose; (c) this latter defect is due to reduced ATP content induced partly by high ICa2+J of islets; and (d) the high [Ca2J1i in islets of CRF rats is due to augmented PTH-induced calcium entry into cells and decreased calcium extrusion from the islets secondary to reduced activity of the Ca2" ATPase. (J. Clin. Invest. 1991. 87:255-261.)

Lymphocytes have receptors for PTH and patients with chronic renal failure have high blood levels of PTH and impaired lymphocyte function. It is possible, therefore, that PTH affects lymphocyte function. We studied the interaction between PTH and proliferation of human lymphocytes in vitro and examined potential mechanisms for such an interaction. 1-84 PTH stimulated in a dose dependent manner PHA-induced proliferation of T cells but had no effect on PWM-induced proliferation. The hormone did not alter CD4/CD8 ratio. Inactivation of PTH abolished its stimulatory effect. PTH augmented IL-2 production by PHA-activated T cells but did not increase expression of IL-2R. 1-34 PTH also stimulated PHA-induced T cell proliferation. TPA augmented PHA-induced T cell proliferation but the addition of PTH to the culture stimulated by PHA and TPA did not augment further the proliferation of T cells. Staurosporin reversed the stimulation by PTH of the PHA-induced lymphocyte proliferation. Both 1-34 and 1-84 PTH stimulated cyclic AMP production by lymphocytes. Forskolin did not affect PHA-induced T cell proliferation although it stimulated cyclic AMP generation. The results show that: 1) PTH acts on T cells; 2) acute exposure to PTH augments PHA-induced T cell proliferation and IL-2 production; 3) this action of PTH is related to its biological activity and is most likely due to the ability of PTH to enhance entry of calcium into cells and/or stimulation of protein kinase C but is independent of cyclic AMP generation.

Indirect evidence indicates that parathyroid hormone (PTH) interacts with pancreatic islets and modulates their insulin secretion. This property of PTH has been implicated in the genesis of impaired insulin release in chronic renal failure. We examined the direct effect of PTH-(1-84) and PTH-(1-34) on insulin release using in vitro static incubation and dynamic perifusion of pancreatic islets from normal rats. Both moieties of the hormone stimulated in a dose-dependent manner glucose-induced insulin release but higher doses inhibited glucose-induced insulin release. This action of PTH was modulated by the calcium concentration in the media. The stimulatory effect of PTH was abolished by its inactivation and blocked by its antagonist [Tyr-34]bPTH-(7-34)NH2. PTH also augmented phorbol ester (TPA)-induced insulin release, stimulated adenosine 3',5'-cyclic monophosphate (cAMP) generation by pancreatic islets, and significantly increased (+50 +/- 2.7%, P less than 0.01) their cytosolic calcium. Verapamil inhibited the stimulatory effect of PTH on insulin release. The data show that 1) pancreatic islets are a PTH target and may have PTH receptors, 2) stimulation of glucose-induced insulin release by PTH is mediated by a rise in cytosolic calcium, 3) stimulation of cAMP production by PTH and a potential indirect activation of protein kinase C by PTH may also contribute to the stimulatory effect on glucose-induced insulin release, and 4) this action of PTH requires calcium in incubation or perifusion media.

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