acetylcellulose and Neutropenia

Haemodialysis membranes with a wide range of solute and hydraulic permeabilities are used clinically. Such membranes are manufactured from either cellulose or synthetic co-polymers and their biocompatibility is commonly characterized by the complement activation and white cell changes observed during their use. The cellobiosic unit may be modified by the partial or total replacement of the hydroxyl groups by diethylaminoethyl (Hemophan), acetate (cellulose acetate), triacetate (cellulose triacetate) or 2,5-acetate (Diaphan). We have undertaken a prospective study in which such renal membranes have been studied in terms of the complement activation and neutropenia produced with the aim of investigating the relationship between modification of the cellobiosic unit and the magnitude of neutropenia and complement activation, and the extent to which membrane base material influences these parameters, by comparing the changes observed in modified cellulose membranes with that for a synthetic membrane (polysulphone). Our findings show that, while the degree of substitution varies between < 1% and total substitution, there is no correlation between the numbers of hydroxyl groups replaced and alteration of complement activation and neutropenia. However, by modification of the cellobiosic unit it is possible to produce a membrane whose biocompatibility is similar to that of a membrane manufactured from a synthetic co-polymer such as polysulphone.

Topics: Biocompatible Materials; Blood Platelets; Cellulose; Complement Activation; Cross-Over Studies; Humans; Leukocyte Count; Leukocytes; Membranes, Artificial; Neutropenia; Platelet Count; Polymers; Prospective Studies; Renal Dialysis; Renal Insufficiency; Sulfones

Complement (C) activation, neutropenia, and mild pulmonary dysfunction attend hemodialysis (HD) with cellophane [for example, cuprophan (Cu)] membranes. While usually asymptomatic, these phenomena may cause distress in patients with cardiopulmonary disease, and "start-up" symptoms of HD might be mediated by C-stimulated granulocytes (PMNs). Cellulose acetate (CA) hemodialysis membranes have been devised and claimed more blood compatible than Cu. In a blinded series of HD patients, pruritus, fatigue, and sense of well-being were each scored statistically more favorably by the patients during HD with CA than during HD with Cu (P less than 0.05). Postulating that less C activation might underlie the benefit, we showed that neutropenia was less severe with CA (nadir 77.6% of initial count, +/- 4 SEM) than with Cu (38.3% +/- 2.9; P less than 0.01). In vitro, incubation of CA membranes with plasma led to less C3 conversion (20% vs. 40%), less PMN aggregating activity (5.9 ZAP units vs. 36.3) and less decrement in CH50 (6.5% vs. 22%) than like incubations of Cu. C activation was also less potent in vivo: During HD plasma C3a rose from a mean 401 ng/ml to a peak 6,325 in patients on Cu dialyzers, but from 426 to only 3,637 in patients on CA devices (P less than 0.05). Time-course studies suggested CA was initially as potent an activator as Cu but rapidly lost ability to activate C, possibly because of saturation of C3b binding sites. As an index of PMN activation, we also assayed plasma lactoferrin and found levels significantly higher during Cu than CA dialysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anaphylatoxins; Biocompatible Materials; Cellulose; Complement Activation; Complement C3; Complement C3a; Complement C5; Complement C5a; Fatigue; Humans; Kidneys, Artificial; Lactoferrin; Lymphocyte Activation; Membranes, Artificial; Neutropenia; Neutrophils; Prospective Studies; Pruritus; Renal Dialysis; Time Factors

Complement activation, neutrophil stimulation, increased cellular adhesiveness, transient leukocyte margination and pulmonary leukostasis take place during hemodialysis with cellulosic dialysis membranes. Several investigators have hypothesized that complement activation is primarily responsible for the acute neutropenia occurring during the early phase of bio-incompatible hemodialysis. We have investigated the relationship between complement activation, levels of expression of CD11b and CD61 integrins on neutrophils and platelets, neutrophil counts and blood gas measurements in patients dialyzed with three types of membranes, known to activate the complement system to a different extent. Polysulfone, cellulose acetate and cuprophane membranes were used subsequently in six patients in a prospective cross-over trial design to reduce inter-individual variability. Increased levels of CD61 and CD11b, as well as neutropenia, were detected regardless of the type of membrane used. We observed a high inter-individual variation with regard to complement activation suggesting varying susceptibility to dialysis membranes. We also report that the kinetics of anaphylatoxin generation were dissociated from those of the upregulation of adhesion molecules, early neutrophil margination and decrease in PaO2 during the first 30 min of hemodialysis. Similar results were obtained with all three types of dialysis membranes. The data strengthen the hypothesis that factors other than complement are involved in the induction of dialysis-related neutropenia and hypoxemia.

Topics: Adult; Anticoagulants; Biocompatible Materials; Cellulose; Complement Activation; Humans; Integrins; Kidney Failure, Chronic; Membranes, Artificial; Middle Aged; Neutropenia; Renal Dialysis; Sulfones

Renal replacement therapy relies predominantly on the use of cellulose-based membranes. Such membranes have a biocompatibility profile which is inferior to membranes manufactured from synthetic polymers. Synthetically modified cellulose (SMC) is a new, low-flux haemodialysis membrane in which hydroxyl groups have been replaced with benzyl groups. The biocompatibility profile characterized by changes in white cell and platelet counts and the activation of complement components (C3a, C5a and C5b-9) have been studied in vivo and compared with those of cellulose acetate, unmodified cellulose (Cuprophan ) and low-flux polysulphone (Fresenius Polysulfone) in the same group of patients. For SMC, the white cell count at 15 min declined to 65.6% of pretreatment level, compared with 63.8% for the cellulose acetate, 79.6% for low-flux polysulphone and 28.1% for Cuprophan, thereafter returning to pretreatment levels. Both modified cellulose membranes were superior to unmodified cellulose (P = 0.001); the differences between the modified cellulose membranes were not significant statistically. The changes induced by all three cellulose-based membranes exceeded those for low-flux polysulphone (P = 0.001). Associated with the neutropenia was a reduction in platelet count, but this was independent of membrane type. The mean time-averaged concentrations of C3a(des Arg) over 150 min were 1168 ng ml(-1) (SMC), 1030 ng ml(-1) (cellulose acetate), 1297 ng ml(-1) (Cuprophan) and 790 ng ml(-1) (low-flux polysulphone). Equivalent values for C5a(des Arg) were 6.12 (SMC), 2.98 (cellulose acetate), 11.03 (Cuprophan) and 1.33 ng ml(-1) (low-flux polysulphone). C5b-9 values were 385 (SMC), 386 (cellulose acetate), 177 (Cuprophan) and 185 ng ml(-1) (low-flux polysulphone). For each of the complement components the differences between the membranes were significant [P = 0.0009 (C3a(des Arg)), P = 0.0001 (c5a(des Arg) and C5b-9)]. The levels of C5b-9 generated during dialysis also showed a significant positive correlation compared to C5a for all membranes considered as a single group (Pearson's correlation coefficient = 0.870, P = 0.0001). It is concluded that the modification of the cellobiosic unit is a promising approach to improve the biocompatibility profile of cellulose-based membranes. The two different methods of modification lead to similar improvements in biocompatibility compared with unmodified cellulose, but as yet do not match that of low-flux polysulphone.

Topics: Biocompatible Materials; Cellulose; Complement Activation; Humans; Leukocyte Count; Membranes, Artificial; Neutropenia; Platelet Count; Polymers; Prospective Studies; Renal Dialysis; Sulfones

To assess the inter-relationship of leucopenia and PMN elastase release we undertook a prospective crossover study of 6 patients dialysed with new and reused cuprophane, cellulose acetate and polysulfone membranes. Serial blood samples were analysed for PMN count, and elastase-alpha 1-proteinase inhibitor complex (E alpha 1PI) concentrations. After 15 min dialysis with new membranes median PMN counts fell by 72.2%, 25.3% and 22.1% with cuprophane, cellulose and polysulfone, respectively. With reuse the decreases were reduced to 6.4%, 8% and 13.6%. All membranes produced a gradual increase of E alpha 1PI. Median E alpha 1PI accumulation rates (ng ml-1 min-1) with new membranes were 175, 169 and 187 for cuprophane, cellulose acetate and polysulfone, respectively. With reuse of cuphrophane and cellulose acetate these rates fell to 99 and 109 (p less than 0.05 and p less than 0.05, respectively), however, with polysulfone it remained unchanged at 180 ng ml-1 min-1. This study highlights differences between two aspects of the neutrophil response to haemodialysis, and demonstrates that extrapolation from individual parameters to conclusions concerning biocompatibility may be inappropriate.

Topics: Adult; Aged; Biocompatible Materials; Cellulose; Female; Filtration; Humans; Leukocyte Count; Male; Membranes, Artificial; Middle Aged; Neutropenia; Neutrophils; Pancreatic Elastase; Polymers; Renal Dialysis; Serine Proteinase Inhibitors; Sulfones

Topics: Cellulose; Complement Activation; Humans; Lactoferrin; Membranes, Artificial; Neutropenia; Neutrophils; Prospective Studies; Renal Dialysis