The transient
granulocytopenia of
hemodialysis results indirectly from plasma complement activation by dialyzer
cellophane membranes. The C5a(desarg) so produced can induce reversible granulocyte aggregation in vitro and in vivo, and we hypothesized that the pulmonary
leukostasis responsible for the
granulocytopenia results from embolization of aggregates formed under the influence of C5a(desarg) produced in the dialyzer. These studies were designed to measure C5a(desarg) generation during dialysis by granulocyte aggregometry and to determine the reason for the transience of the
leukostasis. C5a(desarg) generation was equally evident throughout dialysis, persisting well after
granulocytopenia had reversed, and dialyzer-induced complement activation was insufficient to produce significant depletion of plasma
complement titers. That granulocyte deactivation might be responsible for the transience was suggested by the absence of the usual
granulocytopenia in a patient with uniquely high levels of C5a(desarg) in his predialysis plasma. Granulocytes drawn from seven stable uremic patients after
granulocytopenia had reversed exhibited a dose-related, selective and irreversible refractoriness to stimulation with C5a(desarg), but their responses to n-formyl-
Met-Leu-Phe remained normal. Identical deactivation was produced in normal cells by short- or long-term exposure of C5a(desarg) in vitro. These studies suggest that C5a(desarg) is indeed generated by the dialyzer throughout
hemodialysis and that the transience of the
leukostasis and
granulocytopenia is due to selective down-regulation of cellular responses to C5a(desarg)-a phenomenon that hitherto has been described only in vitro and that may be important in limiting the deleterious effects of adherent granulocytes on the endothelium in patients with intravascular complement activation.