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The ability of three dialysis membranes (cuprophane, cellulose acetate, and polymethylmethacrylate) to activate complement was studied prospectively in ten chronic dialysis patients using new and reused membranes. Patients were dialyzed for 1 month with each type of membrane. New cuprophane membranes caused the most intense activation, while polymethylmethacrylate (PMMA) surfaces caused the least degree of complement activation. Reuse decreases the capacity of the cuprophane membrane to activate complement but does not significantly alter the capacity of cellulose acetate membranes. The extent of complement activation paralleled the ability of these membranes to induce neutropenia. Recurrent dialysis with new cuprophane and cellulose acetate membranes leads to a decrease in pre-dialysis and "rebound leukocytosis" neutrophil count, as well as a more intense activation of complement and an enhanced endogenous clearance of products of complement activation. The clinical sequelae of recurrent complement activation are discussed.
Certain patients receiving hemodialysis experience recurrent chest pain, dyspnea, and hypotension during exposure to new cuprophane-membrane dialyzers (the "first-use syndrome"). Because activation of complement may be involved in these events, we examined in vivo complement activation with new cuprophane membranes and in vitro activation by zymosan in 6 such patients, and compared them with 10 patients who did not have symptoms during dialysis. All patients with the first-use syndrome had maximal complement activation 10 minutes after initiation of dialysis, with C3a des-arginine (desArg), the stable metabolite of C3 activation, equal to 8533 +/- 157 ng per milliliter (mean +/- S.E.M.). In asymptomatic patients the maximal C3a desArg value occurred at 15 minutes and was only 2907 +/- 372 ng per milliliter (P less than or equal to 0.0001). At a concentration of 3.8 x 10(-5) g of zymosan per milliliter, patients with the first-use syndrome had a C3a desArg level of 29.6 +/- 1.4 micrograms per milliliter, whereas it was only 16.6 +/- 2.3 micrograms per milliliter in asymptomatic patients (P less than or equal to 0.0001). Two other patients, who experienced cardiopulmonary collapse during the first two minutes of dialysis, had a C3a desArg level of 18,900 and 7800 ng per milliliter, respectively. We conclude that the occurrence of adverse symptoms associated with new cuprophane-membrane dialyzers correlates with complement activation.
To identify the mechanisms accounting for hemodialysis-induced granulocytopenia, we undertook quantitative kinetic studies of a granulocyte-adhesion-promoting surface glycoprotein (Mo1). In eight patients undergoing maintenance hemodialysis, there was a fivefold increase in the mean cell-surface expression of Mo1 within 15 minutes after the start of dialysis with a new cuprophane membrane. The peak increase in surface Mo1 coincided with the maximal drop in neutrophil count and with the peak rise in the plasma levels of the complement-activation products C5a desArg and C3a desArg. During dialysis on a membrane being reused for the fifth time, no significant complement activation, no increase in Mo1 expression, and no change in neutrophil count were seen. C5a desArg (but not C3a desArg) induced a comparable increase in Mo1 expression on normal granulocytes in vitro at concentrations similar to those measured in vivo. Chemotactic peptide-induced granulocyte aggregation (a reflection of increased cell-to-cell adhesiveness) was specifically blocked by mouse monoclonal antibodies to Mo1 in vitro. These data suggest that the increased expression of Mo1 on granulocytes in vivo is in part mediated by C5a (and C5a desArg). The quantitative increase in granulocyte-surface Mo1 may provide a mechanism for initiating leukoaggregation, sequestration of granulocytes, and neutropenia during hemodialysis.
The spin systems that comprise the 1H nuclear magnetic resonance (NMR) spectrum of the complement fragment C3a (Mr 8900) have been completely identified by an approach which integrates data from a wide range of two-dimensional NMR experiments. Both relayed and multiple quantum experiments play an essential role in the analysis. After the first stage of analysis the spin systems of 60 of the 77 residues were assigned to the appropriate residue type, providing an ample basis for subsequent sequence-specific assignments. Elements of secondary structure were identified on the basis of networks of characteristic sequential and medium-range nuclear Overhauser effects (NOEs), values of 3JHN alpha, and locations of slowly exchanging backbone amide protons. Three well-defined helical segments are found. Gradients of increasing mobility in distinct segments of the C3a polypeptide are observed, with very high mobilities for several residues near the C- and N-termini, including the complete C-terminal receptor binding site pentapeptide LGLAR. The NMR data, combined with known disulfide linkages and a small number of critical long-range NOEs, provide the global folding pattern of C3a in solution. Identical solution structures were found for both the intact active protein and the largely inactive physiologic product des-Arg77-C3a.(ABSTRACT TRUNCATED AT 250 WORDS)