MONOCYTE PHENOTYPES AND MORBIDITY IN UREMIA

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Of the numerous in vitro functional abnormalities observed for leukocytes isolated from patients with renal failure, monocyte dysfunction has the greatest capacity to predict a clinically significant infectious event in vivo. Many of these monocyte functional abnormalities resemble those observed with inadequate nutrition. Because dialysis with certain membranes results in the abnormal release of monocyte-derived cytokines which have a catabolic effect on intermediary metabolism, it has been suggested that dialysis per se may be provocative for the development of malnutrition. Therefore, we suggest that the functional phenotype of the monocyte is a critical determinant of infectious and nutritional morbidity in dialysis patients. We propose that the phenotype of monocyte associated with this excessive risk can be defined in vitro and will provide a premorbid marker of the patient at risk. Further, defining such a phenotype will permit an in vitro analysis of the capacity of monocyte-directed regulatory cytokines to correct the abnormal function. Pursuant to these aims, we propose a prospective, cross-over study in which patients are dialyzed on membranes composed of cuprophane, cellulose acetate, polyacrylonitrile, and polysulfone. Monocytes will be isolated for phenotypic analysis during the six months of dialysis on each membrane; monocyte phenotyping will be based upon the kinetics of programmed cell death, and their capacity to elaborate select nutritionally relevant cytokines, proinflammatory lipids and reactive oxygen species, to mediate cytotoxicity, and to function as antigen presenting cells. The abnormal monocyte phenotypes will be correlated with patient outcome, defined by infectious complications and inclusive nutritional parameters of urea kinetic modelling, plasma levels of select proteins, in vivo immunologic assessment, and dietary history.