Reversal of Hemodialysis Granulocytopenia and Pulmonary Leukostasis: A CLINICAL MANIFESTATION OF SELECTIVE DOWN-REGULATION OF GRANULOCYTE RESPONSES TO C5a_desarg

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Abstract

The transient granulocytopenia of hemodialysis results indirectly from plasma complement activation by dialyzer cellophane membranes. The C5adesarg 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 C5adesarg produced in the dialyzer. These studies were designed to measure C5adesarg generation during dialysis by granulocyte aggregometry and to determine the reason for the transience of the leukostasis. C5adesarg 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 C5adesarg 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 C5adesarg, 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 C5adesarg in vitro. These studies suggest that C5adesarg 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 C5adesarg—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.

Authors

Keith M. Skubitz, Philip R. Craddock