Background/Aim: Transient leukopenia during hemodialysis due to neutrophil activation is attributed to bioincompatibility of the dailysis membrane, but the mechanism remains unclear. We studied the mechanism of neutrophilic activation by comparing a vitamin E modified membrane (CLEE) and a regular cellulose membrane (CLSS). Methods: (1) CLSS and CLEE membranes were used in a crossover clinical study in 7 chronic hemodialysis patients. Neutropenia, CD11b expression, and plasma C3a and myeloperoxidase concentrations were compared between the two dialyzer membranes. (2) Normal blood was circulated through CLEE and CLSS minimodels, and the same parameters were compared. (3) Blood samples with modified complement activities (EDTA: both classical and alternative pathways inactivated; EGTA+Mg: classical pathway inactivated; heating: alternative pathway inactivated; control: no modification) were incubated in the CLSS minimodel, and the neutrophilic activation was compared. Results: In clinical hemodialysis, neutropenia, CD11b expression, and C3a and myeloperoxidase levels were significantly lower when CLEE membranes were used. The same tendency was observed in minimodels. However, the degrees of inhibition in clinical dialysis, especially at the venous line, were significantly higher than in minimodels. As compared with controls, CD11b expression and myeloperoxidase level were significantly lower when both classical and alternative pathways were inactivated or when the classical pathway alone was inactivated, but were not significantly different when the alternative pathway alone was inactivated. Conclusions: Vitamin E modification of the dialyzer reduces some reactions of neutrophilic activation, such as CD11b expression and myeloperoxidase release, more effectively in the clinical situation than in ex vivo models, suggesting a possible effect of vitamin E in inhibiting bioreactions due to pyrogen in the dialysate. The classical complement pathway is required in membrane-induced neutrophilic activation, at least during the initial stage.

Kaplow L, Goffinet J: Profound neutropenia during the early phase of hemodialysis. JAMA 1968;203:1135–1137.
Arnaout MA, Hakim RM, Todd RF 3rd, Dana N, Colten HR: Increased expression of an adhesion-promoting surface glycoprotein in the granulocytopenia of hemodialysis. N Engl J Med 1985;312:457–462.
Himmelfarb J, Zaoui P, Hakim R, Holbrook D: Modulation of granulocyte LAM-1 and MAC-1 during dialysis: A prospective randomized controlled trial. Kidney Int 1992;41:388–395.
Tielemans CL, Delville J-PC, Husson CP, Madhoun P, Lambrechts AM, Goldman M, Vanherweghem JL: Adhesion molecules and leukocyte common antigen on monocytes and granulocytes during hemodialysis. Clin Nephrol 1993;39:158–165.
Lundahl J, Hed J, Jacobson SH: Dialysis granulocytopenia is preceded by an increased surface expression of the adhesion-promoting glycoprotein Mac-1. Nephron 1992;61:163–169.
Bentwood BJ, Henson PM: The sequential release of granule constituents from human neutrophils. J Immunol 1980;124:855–862.
Akiko S, Ken K, Masayuki K: Impaired neutrophil function in chronic renal failure: Dysregulation of surface adhesion molecule expression and phagocytosis. Jpn J Nephrol 1996;38:585–594.
Campistol JM, Molina R, Bernard DB, Rodriguez R, Mirapeix E, Muñoz-Gómez JM, Revert L: Synthesis of beta 2-microglobulin in lymphocyte culture: Role of hemodialysis, dialysis membranes, dialysis-amyloidosis, and lymphokines. Am J Kidney Dis 1993;22:691–699.
Aljama P, Bird PA, Ward MK, Feest TG, Walker W, Tanboga H, Sussman M, Kerr DN: Hemodialysis-induced leukopenia and activation of complement: Effects of different membranes. Proc Eur Dial Transplant Assoc 1978;15:144–153.
Craddock PR, Fehr J, Dalmasso AP, Brighan KL, Jacob HS: Hemodialysis leukopenia: Pulmonary vascular leukostasis resulting from complement activation by dialyzer cellophane membranes. J Clin Invest 1977;59:878–888.
Pettersen HB, Johnson E, Hetland G: Human alveolar macrophages synthesize active complement components C6, C7 and C8 in vitro. Scand J Immunol 1987;25:567–570.
Peuchant E, Carbonneau MA, Dubourg L, Thomas MJ, Perromat A, Vallot C, Clerc M: Lipoperoxidation in plasma and red blood cells of patients undergoing haemodialysis: Vitamins A, E, and iron status. Free Radic Biol Med 1994;16:339–346.
Paul JL, Sall ND, Soni T, Poignet JL, Lindenbaum A, Man NK, Moatti N, Raichvarg D: Lipid peroxidation abnormalities in hemodialyzed patients. Nephron 1993;64:106–109.
Boscoboinik D, Szewczyk A, Hensey C, Azzi A: Inhibition of cell proliferation by α-tocopherol: Role of protein kinase C. J Biol Chem 1991;266:6188–6194.
Faruqui R, Motte C, Di Corleto PE: α-Tocopherol inhibits agonist-induced monocytic cell adhesion to cultured human endothelial cells. J Clin Invest 1994;94:592–600.
Ozer NK, Palozza P, Boscoboinic D, Azzi A: d-α-Tocopherol inhibits low density lipoprotein induced proliferation and protein kinase C activity in vascular smooth muscle cell. FEBS Lett 1993;322:307–310.
Higuchi C, Ishimori I, Hutatsuyama K, Kaneko I, Sanaka T, Nihei H, Uchiyama H: Evaluation of the biocompatibility of a dialyzer (the Cl-ES15) employing the vitamin E-bonded membrane. Excebrane 1996.
Savenkova MI, Mueller DM, Heinecke JW: Tyrosyl radical generated by myeloperoxidase is a physiological catalyst for the initiation of lipid peroxidation in low density lipoprotein. J Biol Chem 1994;269:20394–20400.
Buettner GR: The pecking order of free radicals and antioxidants: Lipid peroxidation, α-tocopherol, and ascorbate. Arch Biochem Biophys 1993;300:535–543.
Kawabata K, Nagake Y, Shikata K, Makino H, Ota Z: The changes of Mac-1 and L-selectin expression on granulocytes and soluble L-selectin level during hemodialysis. Nephron 1996;73:573–579.
Akeson AL, Woods CW, Mosher LB, Thomas CE, Jackson RL: Inhibition of IL-1β expression in THP-1 cells by probucol and tocopherol. Atherosclerosis 1991;86:261–270.
Suzuki YJ, Packer L: Inhibition of NF-κB activation by vitamin E derivatives. Biochem Biophys Res Commun 1993;193:277–283.
Manning AM, Bell FP, Rosenbloom CL, Chosay JG, Simmons CA, Northrup JL, Shebuki RJ, Dunn CJ, Anderson DC: NF-κB is activated during acute inflammation in vivo in association with elevated endothelial cell adhesion molecule gene expression and leukocyte recruitment. J Inflamm 1995;45:283–296.
Zhou L, Pope BL, Chourmouzis E, Fung-Leung W-P, Lau CY: Tepoxalin blocks neutrophil migration into cutaneous inflammatory sites by inhibiting Mac-1 and E-selectin expression. Eur J Immunol 1996;26:120–129.
Urena P, Herbelin A, Zingraff J, Lair M, Man NK, Descamps-Latscha B, Drüeke T: Permeability of cellulosic and non-cellulosic membranes to endotoxin subunits and cytokine production during in vitro hemodialysis. Nephrol Dial Transplant 1992;7:16–28.
Vanholder R, Van Haecke E, Veys N, Ringoir S: Endotoxin transfer through dialysis membranes. Nephrol Dial Transplant 1992;7:333–339.
Mitzner S, Stange J, Pichel K, Handschuk I, Korten G, Ehlers M, Schut C, Schmidt R: Increased soluble CD14 levels in patients on hemodialysis: Influence of dialysate endotoxin or incompatibility to dialyzer membranes? ASAIO J 1995;41:M707–M708.
Knudsen PJ, Leon J, Ng A, Shaldon S, Floege J, Koch KM: Hemodialysis-related induction of beta-2-microglobulin and interleukin-1 synthesis and release by mononuclear phagocytes. Nephron 1989;53:188–193.
Cavaillon NH, Cavaillon JM, Ciancioni C, Bacle F, Delsons S, Kazatchkine MD: In vivo induction of interleukin-1 during hemodialysis. Kidney Int 1989;35:1212–1218.
Masakane I, Matsunaga T, Yakubi S. Jpn J Nephrol 1997;39:243.
Baz M, Durand C, Ragon A, Jaber K, Andrieu D, Merzouk T, Purgus R, Olmer M, Reynier JP, Berland Y: Using ultrapure water in hemodialysis delays carpal tunnel syndrome. Int J Artif Organs 1991;14:681–685.
Schindler R, Lonnemann G, Shaldon S, Koch K-M, Dinarello ChA: Transcription, not synthesis, of interleukin-1 and tumor necrosis factor by complement. Kidney Int 1990;37:85–93.
Hakim RM: Clinical implications of hemodialysis membrane biocompatibility. Kidney Int 1993;44:484–494.
Himmelfarb J, McMonagle E, Holbrook D, Toth C: Soluble complement receptor 1 inhibits both complement and granulocyte activation during ex vivo hemodialysis. J Lab Clin Med 1995;126:392–400.
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