Background: Platelet-activating factor (PAF) production during hemodialysis (HD) with cuprophane (CU) membrane has previously been demonstrated, while the results regarding PAF production during HD with AN-69 polyacrylonitrile membrane are dubious. In this study an attempt is made to show that PAF is produced during HD using AN-69 membrane while comparing this production with the corresponding one from HD with CU. Since previous studies have indicated that PAF, like the complement system, could also be implicated in HD-related leukopenia and thrombocytopenia (especially when CU membrane is used), the circulating leukocyte and platelet counts as well as the C3a-desArg and SC5b-9 (soluble, nonlytic form of the terminal complement complex) levels were measured. Methods: Ten hemodialyzed patients were subjected to HD with CU and AN-69 membranes for 2 consecutive weeks (first week with CU and second with AN-69). During the third HD session of each week and at different times (0, 2, 5, 15, 30, 60, 180 and 240 min), the PAF levels in the blood as well as the leukocyte and platelet counts were measured, while the circulating levels of the C3a-desArg and SC5b-9 were measured at 0, 5, 15, 60 and 240 min. PAF was detected by ethanol extraction, followed by purification by column chromatography and high-pressure liquid chromatography and finally quantified by bioassay. The C3a-desArg and SC5b-9 fractions of the complement were measured by immunoassay while an autoanalyzer gave the leukocyte and platelet counts. Results: Circulating PAF levels were detected at all time intervals during HD with AN-69 (PAFAN-69) and CU (PAFCU) membranes. At all time intervals PAFAN-69 < PAFCU, however, statistically significant differences (s) between the two membranes existed only at 15, 30, 60, 180 and 240 min. The highest PAFAN-69 and PAFCU occurred at 5 and 15 min into dialysis, respectively. The same observations were made for circulating C3a-desArg levels (s existed additionally at 5 min as well). The reduction of the circulating leukocytes had almost a mirror image with the C3a-desArg as well as PAF levels while the maximal reduction of platelets was observed after 2 min into dialysis with both membranes (i.e., simultaneously with the first increase in PAF secretion). Conclusions: PAF is indeed produced during HD with AN-69 membrane, as it is during HD with CU. At all time intervals during the HD procedure, PAFAN-69 < PAFCU. PAF seems to contribute to HD-related leukopenia and thrombocytopenia with both membranes.

Keywords:
AN-69, Hemodialysis, PAF, PAF-acether, Polyacrylonitrile, Biocompatibility, Leukopenia, Thrombocytopenia
1.
Schulman G, Hakim RM: Recent advantage in the biocompatibility of haemodialysis membranes. Nephrol Dial Transpl 1992 (suppl 2):10–13.
2.
Cheung AK, Leypoldt JK: The hemodialysis membranes: A historical perspective, current state and future prospect. Semin Nephrol 1997;17:196–213.
3.
Pinckard RN, McMunus L, Hanahan DJ: Chemistry and biology of acetyl glyceryl ether phosphorylcholine (platelet-activating factor). Adv Inflam Res 1982;4:147–180.
4.
Schlondorff D, Neuwirth R: Platelet-activating factor and the kidney. Am J Physiol 1986;251:F1–F11.
5.
Camussi G: Potential role of platelet-activating factor in renal pathophysiology (editorial). Kidney Int 1986;29:469–477.
6.
Braquet P, Guinot P, Touvay C: The role of PAF-acether in anaphylaxis demonstrated with the use of the antagonist BN 52021. Agents Actions Suppl 1987;21:97–117.
7.
Camussi G, Tetta C, Baglioni C: The role of platelet-activating factor in inflammation. Clin Immunol Immunopathol 1990;57:331–338.
8.
Madrenas J, Pintos Morell G, Bratolome E et al: PAF-acether (platelet-activating factor) and biocompatibility of hemodialysis membranes. Kidney Int 1987;32:614.
9.
Tetta C, Segoloni G, Pacitti A et al: The production of platelet-activating factor during hemodialysis. Int J Artif Organs 1989;12:766–772.
10.
Sakaguchi K, Morimoto S, Chen YH, Nakamoto Y, Ogihara T: Increases in circulating level of platelet-activating factor lag behind transient neutropenia during hemodialysis with cuprophane membrane. Nephron 1991;59:455–460.
11.
Iatrou C, Afentakis N, Antonopoulou S, Andrikopoulos N, Demopoulos CA, Ziroyannis P: The production of platelet-activating factor during hemodialysis with cuprophane membrane. Does the calcium concentration in the dialysate play any role on it? Intern J Artif Organs 1995;18:355–361.
12.
Cuastoni C, Tetta C, Hoenich NA et al: Mechanisms and kinetics of the synthesis and release of platelet-activating factor by polyacrylonitrile membranes. Clin Nephrol 1996;46:132–138.
13.
Graddock PR, Fehr J, Dalmasso AP, Brigham KL, Jacobs HS: Hemodialysis leukopenia. Pulmonary vascular leukostasis resulting from complement activation by dialyzer cellophane membranes. J Clin Invest 1977;59:879–888.
14.
Craddock PR, Fehr J, Brighman KL, Kronenberg RJ, Jacob HJ: Complement and leukocyte-mediated pulmonary dysfunction in hemodialysis. N Engl J Med 1977;296:769–774.
15.
Cheung AK, Chenoweth DE, Otsuka D, Henderson LW: Compartmental distribution of complement activation products in artificial kidneys. Kidney Int 1986;30:74–80.
16.
Polley MJ, Nachman RL: Human platelet activation by C3a and C3a des-arg. J Exp Med 1983;158:603–615.
17.
Camussi G, Segoloni G, Rotunno M, Varcellone A: Mechanism involved in acute granulocytopenia in hemodialysis. Cell-membrane direct interactions. Int J Artif Organs 1978;3:123–127.
18.
Camussi G, Pacitti A, Tetta C et al: Mechanisms of neutropenia in hemodialysis. Trans Am Soc Artif Intern Organs 1984;30:364–369.
19.
Tetta C, Jeantet A, Camussi G et al: Direct interaction between polymorphonuclear neutrophils and cuprophane membrane in a plasma-free model of dialysis. Proc Eur Dial Transplant 1984;21:150–155.
20.
Demopoulos CA, Andrikopoulos NK, Antonopoulou S: Simple and precise method for the routine determination of platelet-activating factor in blood and urine. Lipids 1994;29:305–309.
21.
Bligh EO, Dyer WJ: A rapid method of total lipid extraction and purification. Can J Biochem Physiol 1959;37:911–917.
22.
Demopoulos CA, Pinckard NR, Hanahan DJ: Platelet-activating factor. Evidence for 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine as the active component (a new class of lipid chemical mediators). J Biol Chem 1979:254:9355–9358.
23.
Conzalez-Lopez A, Fernandez-Gallardo S, Caramelo C, Inarrea P, Hernando L, Sanchez Crespo M: Presence of PAF acether in blood during hemodialysis and its relation with dialysis leukopenia. Kidney Int 1985;28:587.
24.
Cristol JP, Canaud B, Damon M, Chavis C, Arnoux B, Mion C: Platelet-activating factor production during hemodialysis: Effect of BN52021. Prostaglandins Leukot Essent Fatty Acids 1992;45:37–42.
25.
Chenoweth DE, Cheung AK, Henderson LW: Anaphylatoxin formation during hemodialysis: Effects of different dialyzer membranes. Kidney Int 1983;24:764–769.
26.
Ivanovich P, Chenoweth DE, Schmidt R et al: Symptoms and activation of granulocytes and complement with two dialysis membranes. Kidney Int 1983;24:758–763.
27.
Chenoweth DE, Cheung Ak, Ward DM, Henderson LW: Anaphylatoxin formation during hemodialysis: Comparison of new and re-used dialyzers. Kidney Int 1983;24:770–774.
28.
Vasco M, Rosa M, Levi G, Cerqueira M: The influence of the geometry of the dialyzer and the composition of the dialysate in activating the complement system. Nephron 1990;54:26–31.
29.
Hauser AC, Derfler K, Stockenhuber F, Janata O, Balcke P: Generation of the membrane attack complex during haemodialysis: Impact of classical and alternative pathway components. Clin Sci 1990;79:471–476.
30.
Deppisch R, Schmitt V, Bommer J, Hansch GM, Ritz E, Rauterberg EW: Fluid phase generation of terminal complement complex as a novel index of biocompatibility. Kidney Int 1990;37:696–706.
31.
Shaefer RM, Rauterberg EW, Deppisch R, Vienken J: Assembly of terminal SC5b-9 complement complexes: A new index of blood-membrane interaction. Miner Electrolyte Metab 1990;16:73–76.
32.
Pertosa G, Tarantino EA, Gesualdo L, Montinaro V, Schena FP: C5b-9 generation and cytokine production in hemodialyzed patients. Kidney Int 1993;43(suppl 41):S221–S225.
33.
Mujais SK; Schmidt B, Hacker H, Opatrny K, Gurland HJ: Synthetic modification of PAN membrane: Biocompatibility and functional characterization. Nephrol Dial Transplant 1995;10(suppl 3):46–51.
34.
Johnson RJ: Complement activation during extracorporeal therapy: Biochemistry, cell biology and clinical relevance. Nephrol Dial Transplant 1994;9(suppl 2):36–45.
35.
Weisberg AS, Henle RW, Hannah RT: Transfusion of leukocytes and products of disintegrated leukocytes. Proc Soc Exp Biol Med 1979;10:149–153.
36.
Haag-Weber M, Hable M, Schollmeyer P, Hoerl WH: Metabolic responses of neutrophils to uremia and dialysis. Kidney Int 1989;36(suppl 27):S293–S298.
37.
Hoerl WH, Feinstein EL, Wanner C, Frischmuth N, Goesche A, Massry SG: Plasma levels of main granulocyte components during hemodialysis. Comparison of new reused dialyser. Am J Nephrol 1990;10:53–57.
38.
Hoerl WH, Riegel W, Schollmeyer P, Rautenberg W, Neumann S: Different complement and granulocyte activation dialysed with PMMA dialysers. Clin Nephrol 1986;25:304–307.
39.
Venge P, Olsson I: Cationic proteins of human granulocytes: Effects on the complement system and mediation of chemotactic activity. J Immunol 1975;115:1505–1508.
40.
Camussi G, Mencia-Huerta JM, Benveniste J: Release of platelet-activating factor and histamine. I. Effect of immune complexes, complement and neutrophils on human and rabbit mastocytes and basophils. Immunology 1977;33:523–533.
41.
Camussi G, Tetta C, Bussolino F et al: Mediators of immune complex-induced aggregation of polymorphonuclear neutrophils. I. C5a anaphylotoxin neutrophil cationic proteins and their cleavage fragments. Int Arch Allergy Appl Immunol 1980;62:1–15.
42.
Skubitz KM, Craddock PR: Reversal of hemodialysis granulocytopenia and pulmonary leukostasis. J Clin Invest 1981;67:1383–1391.
43.
Hakim RM, Schafer AL: Hemodialysis-associated platelet activation and thrombocytopenia. Am J Med 1985;78:575–580.
44.
Schmitt GW, Moake JL, Rudy CK, Vicks SL, Hamburger RJ: Alterations in hemostatic parameters during hemodialysis with dialyzers of different membrane composition and flow design. Platelet activation and factor VIII-related von Willebrand factor during hemodialysis. Am J Med 1987;83:411–418.
45.
Sreeharan N, Crow MJ, Salter MC, Donaldson DR, Rarjah SN, Davison MA: Membrane effect on platelet function during hemodialysis: A comparison of cuprophane and polycarbonate. Artif Organs 1982;6:324–327.
46.
Ward RA, Schaefer RM, Falkenhagen D et al: Biocompatibility of a new high-permeability modified cellulose membrane for haemodialysis. Nephrol Dial Transplant 1993;8:47–53.
47.
Lindsay RM, Prentice CRM, Ferguson D, Muir VM, McNicol GP: A method for measurement of platelet adhesiveness by use of dialysis membranes in a test-cell. Br J Haematol 1973;24:377–389.
48.
Lindsay RM, Prentice CRM, Burton JA, Ferguson D, Kennedy AC: A role of the platelet-dialysis membrane interaction in thrombus formation and blood loss during hemodialysis. Trans Am Soc Artif Intern Organs 1973;19:478–491.
49.
Brandt P, Jesperson J, Sorensen LH: Antithrombin-III and platelets in haemodialysis patients. Nephron 1981;28:1–3.
50.
Tielemans C, Madhoun P, Lenaers M, Schandene L, Goldman M, Vanherweghem JL: Anaphylactoid reactions during hemodialysis on AN69 membranes in patients receiving ACE inhibitors. Kidney Int 1990;38:982–984.
51.
Parnes EL, Shapiro WB: Anaphylactoid reactions in hemodialysis patients treated with the AN69 dialyzer. Kidney Int 1991;40:1148–1152.
52.
Brunet P, Jaber K, Berland Y, Baz M: Anaphylactoid reactions during hemodialysis and hemofiltration: Role of associating AN69 membrane and angiotensin I-converting enzyme inhibitors. Am J Kidney Dis 1992;19:444–447.
53.
Schwarzbeck A, Wittenmeier KW, Hallfritzsch U: Anaphylactoid reactions, angiotensin-converting enzyme inhibitors and extracorporeal hemotherapy. Nephron 1993;65:499–500.
54.
Lemke HD, Fink E: Accumulation of bradykinin formed by the ACE inhibitor in vitro. J Am Soc Nephrol 1992;376:115.
55.
Verresen L, Fink E, Lemke HD, Vanrenterghem Y: Bradykinin is a mediator of anaphylactoid reactions during hemodialysis with AN69 membranes. Kidney Int 1994;45:1497–1503.
56.
Schaefer RM, Fink E, Schaefer L, Barkhausen R, Kulzer P, Heidland A: Role of bradykinin in anaphylactoid reactions during hemodialysis with AN69 dialyzers. Am J Nephrol 1993;13:473–477.
57.
Gavras I: Bradykinin-mediated effect of ACE inhibition. Kidney Int 1992;42:1020–1029.
58.
Bhoola KD, Figueroa CD, Worthy K: Bioregulation of kinins: Kallikreins, kininogens, and kininases. Pharmacol Rev 1992;44:1–80.
59.
Snyder F: Platelet-activating factor and related acetylated lipids as potent biological acting cellular mediators. Am J Physiol 1990;259:697–708.
60.
McIntyre TM, Zimmerman GA, Satoh K, Prescott SM: Cultured endothelial cells synthesize both platelet-activating factor and prostacyclin in response to histamine, bradykinin, and adenosine triphosphate. J Clin Invest 1985;76:271–280.
61.
Van der Niepen P, Sennesael J, Verbeelen D, Van Ingelgem D: Prevention of anaphylactoid reactions to high-flux membrane dialysis and ACE inhibitors by calcium. Nephrol Dial Transplant 1993;9:87–89.
62.
Van der Niepen P, Sennesael JJ, Verbeelen DL: Kinin kinetics during different dialysis protocols with AN69 dialyser in ACEI-treated patients. Nephrol Dial Transplant 1995;10:1689–1695.
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