In vitro performance characteristics of a high-flux hemodialyzer with a novel polyester-polymer-alloy (PEPA) membrane.

Despite improvements in hemodialyzers with respect to their clearance of middle and high molecular mass molecules, accumulation of specific solutes in the circulation of dialysis patients continues to be a medical problem. A new membrane material, polyester-polymer alloy (PEPA) which has been developed to have a filtration profile akin to that of the natural kidney, is now being used in hemodialyzers. This study evaluates the performance of a PEPA-based hemodialyzer alongside a selection of available competing high-flux dialyzers using official standardized methods. The new membrane material appears to be a viable alternative which offers performance at least as good as that of the competition. The promising results obtained with the PEPA membrane suggest that a detailed clinical performance study should be undertaken.

Influence of dialysis modalities on serum AGE levels in end-stage renal disease patients.

BACKGROUND: The accumulation of advanced glycation end-products (AGEs) in end-stage renal disease (ESRD) influenced by dialysis modalities is of current interest. Highly permeable membranes in haemodialysis or haemofiltration should be able to eliminate circulating AGEs as well as their AGE precursors more efficiently. METHODS: In our study, 10 non-diabetic and 10 diabetic ESRD patients were on haemodialysis with low-flux membranes (LF) followed by a cross-over haemodialysis with high-flux or super-flux polysulfone membranes (HF, SF) for 6 months each. We measured the protein-bound pentosidine and free pentosidine serum levels by high-performance liquid chromatography (HPLC) as well as the serum AGE peptide, AGE-beta(2)-microglobulin and beta(2)-microglobulin concentrations, using ELISA assays. RESULTS: All parameters investigated were significantly higher in dialysis patients than in healthy subjects. The reduction rates during a single dialysis session were found to be higher using the SF than those obtained with the HF (free pentosidine 82.4+/-7.3 vs 76.6+/- 8.7%; AGE peptides 79.7+/-7.7 vs 62.3+/-14.7%; AGE-beta(2)-microglobulin 64.0+/-16.5 vs 45.4+/-17.7%; beta(2)-microglobulin 70.5+/-5.6 vs 58.2+/-6.0%). The protein-bound pentosidine levels remained constant over the respective dialysis sessions. In the 6-month treatment period with the SF, decreased pre-dialysis serum levels of protein-bound pentosidine, free pentosidine and AGE peptides were observed in non-diabetics and diabetics as compared with values obtained with the LF. The respective pre-dialysis AGE-beta(2)-microglobulin concentrations decreased insignificantly, whereas those of beta(2)-microglobulin were significantly lower. Using the HF dialyser, only moderate changes of the parameters measured were noted. CONCLUSION: Treatment with the biocompatible polysulfone SF dialyser seems to be better suited to lower serum AGE levels and to eliminate their precursors.

Ex vivo complement protein adsorption on positively and negatively charged cellulose dialyser membranes.

An ex vivo test system was used to measure complement protein C3 and factor B adsorption onto small dialyser modules made from regenerated and modified cellulosic hollow fibre membranes in which positive diethylaminoethyl (DEAE) or negative carboxymethyl (CM) groups were introduced into the cellulose matrix. The extracorporeal system, which included test-dialysers and the dialysis environment, allowed the use of labelled proteins without contaminating the blood donors which were connected in an open-loop fashion to the extracorporeal test system. The modules were removed at selected time points from the extracorporeal system for radioactivity counting. The results were used to evaluate the mechanisms involved in complement reactions to foreign surfaces. The system therefore allowed the analysis of complement protein adsorption occurring in the dialyser modules and its relationship to the complement generation rate in the extracorporeal system to be evaluated. It was possible to demonstrate that significant complement C3 and factor B adsorption occurred in the test modules made of cellulosic membranes. Complement adsorption as a function of the pH and the release reaction of the adsorbed C3 and factor B after membrane blood perfusion were therefore found to be variable according to the cellulosic membrane type and the presence of positive or negative charged groups within the cellulose matrix. The data obtained from the ex vivo model therefore provided additional evidence on the discussion of the mechanisms involved in the increased complement activation by regenerated cellulose and in its attenuation by DEAE- or CM-modified cellulose.

Effect of glucose and pyruvate in acidic and non-acidic peritoneal dialysis fluids on leukocytes cell functions.

A new peritoneal dialysate containing pyruvate anions has been tested for its effects on cell functions and compared with conventional lactate and bicarbonate based solutions. The dialysate has a final pH of 5.4 to 5.6 and is composed of 1.36 to 3.86% glucose-monohydrate, 132 mmol/liter sodium, 1.75 mmol/liter calcium, 0.75 mmol/liter magnesium, 102 mmol/liter chloride and 35 mmol/liter pyruvate. For cytotoxicity testing peritoneal macrophages and peripheral blood mononuclear cells (PBMC) were exposed to conventional lactate dialysate, pyruvate dialysate, bicarbonate dialysate and a control medium RPMI 1640 (Biochrom KG, Berlin, Germany), followed by activation with different bacterial stimuli. In addition, the study further investigated the effect of varying glucose concentration in the different dialysates ranging from 0 to 3.86% and pH changes between 5.2 and 7.4 on the cytotoxicity effect on the selected cells. Mononuclear cells exposed to pyruvate-based dialysate before stimulation with endotoxin exhibited a tumor necrosis factor (TNF)-mRNA signal comparable to those of cells exposed to RPMI. In contrast, exposure to lactate-based dialysate completely inhibited TNF-mRNA synthesis. In addition, cytokine synthesis in macrophages and PBMCs after exposure to pyruvate was less inhibited when compared to the corresponding levels measured after exposure to lactate. The chemotactic response of polymorphonuclear cells and O-2 generation in all tested cell types after exposure to pyruvate was found not to be inhibited, whereas a complete inhibition was observed after exposure to lactate. The results demonstrate that cytotoxicity effects of peritoneal dialysate on cell lines can be minimized by using a new dialysate formulation containing pyruvate anions instead of lactate.

The influence of biomaterials on inflammatory responses to cardiopulmonary bypass.

The nature of cardiopulmonary bypass and the complexity of the inflammatory response make the detection and interpretation of a biomaterial influence difficult. However, if mediation of the inflammatory response is considered to be an appropriate clinical goal, alteration to the biomaterial influence merits further investigation.

Retention of cytokine-inducing substances inside high-flux dialyzers.

Reprocessing of dialyzers is often performed with nonsterile solutions possibly contaminated with bacterial-derived cytokine-inducing substances. We investigated the retention of cytokine-inducing substances inside the dialyzer during reprocessing in a closed loop in vitro hemodialysis system using a polyamide high flux membrane. After the first in vitro circulation of human whole blood, rinse of the blood compartment (BC) and reverse ultrafiltration (RUF) was performed with either cytokine-inducing substance-free saline or saline contaminated with filtrates from Pseudomonas cultures (6 ng/ml LAL-reactive material); subsequently, dialyzers were stored in 2% formaldehyde. Dialyzers were rinsed with approximately 15 liters pyrogen-free saline before the second circulation using blood from the same donor; the effluates were free of cytokine-inducing substances and formaldehyde. Before and after the blood circulations, peripheral blood mononuclear cells (PBMC) were separated and total production of IL-1 alpha and IL-1 beta was determined after overnight incubation. In noncirculated PBMC as well as in PBMC separated after whole blood circulation with pyrogen-free processed dialyzers, production of IL-1 beta was not detectable. After contaminated rinse of the BC, production of IL-1 beta could be observed (1,600 +/- 1,100 pg/ml, mean +/- SEM). When pyrogen-free RUF was performed after contaminated BC rinse, IL-1 beta production averaged 163 +/- 92 pg/ml when using reused dialyzers, but 1,820 +/- 880 pg/ml when using new dialyzers. After reuse with pyrogen-free BC-rinse and contaminated RUF no IL-1 beta synthesis was observed; however, when pyrogen-free BC-rinse and contaminated RUF was applied to new dialyzers, IL-1 beta synthesis averaged 1,620 +/- 1,200 pg/ml. We conclude that cytokine-inducing substances are retained inside the dialyzer, probably by adsorption to the membrane as well as to the protein layer covering the membrane and are still biologically active after sterilisation. Cytokine-inducing substances adsorbed to the protein layer can be partially removed by RUF. Finally, the protein layer on the membrane appears to reduce the convective transfer of cytokine-inducing substances from the dialysate into the blood compartment.

Interleukin-1 beta stimulates glucose uptake of human peritoneal mesothelial cells in vitro.

To investigate whether the glucose uptake (GU) of human peritoneal mesothelial cells (HPMC) is mediated by glucose transporters and whether this uptake is influenced by interleukin 1-beta (IL-1 beta), we measured 2-deoxy-(3H)-GU of HPMC in vitro, after exposing the cells for different times (two and 12 hours) to increasing concentrations (0.1, 1.0, and 2.0 ng/mL) of IL-1 beta. To exclude a noncarrier-mediated transport, GU was also tested in the presence of cytochalasin B. All experiments were performed in triplicate in the cells of two donors. Cytochalasin B inhibits GU of HPMC almost completely. GU of HPMC is not stimulated by insulin. GU is stimulated by IL-1 beta in a dose-dependent manner. These data indicate a GU of HPMC, which is mediated by a glucose transporter and stimulated by IL-1 beta. The increased uptake of glucose from the dialysate in patients with peritonitis may be mediated by a (cytokine-induced) increased activity of HPMC glucose transporters.

Induction of interleukin-1 and interleukin-1 receptor antagonist during contaminated in-vitro dialysis with whole blood.

BACKGROUND: Previous studies on the permeability of cellulosic and synthetic dialysers for bacterial-derived cytokine-inducing substances gave conflicting results. We tried to study this issue as close to the in-vivo situation as possible. METHODS: An in-vitro dialysis circuit with whole human blood present in the blood compartment of cuprophane (Cup), polysulphone (PS), and polyamide (PA) dialysers was employed; sterile filtrates derived from Pseudomonas aeruginosa cultures were added to the dialysate. We studied the induction of interleukin-1 beta (IL-1 beta) by plasma samples taken from the blood compartment as well as the induction of IL-1 beta and interleukin-1 receptor antagonist (IL-1Ra) in mononuclear cells separated from whole blood after circulation by radioimmunoassay and polymerase chain reaction. RESULTS: Plasma samples from the blood side of all dialysers induced IL-1 beta from non-circulated mononuclear cells after addition of pseudomonas filtrates to the dialysate; the maximal amount of IL-1 beta induced by samples from the blood compartment was 4.8 +/- 1.2 ng/ml for Cup, 1.9 +/- 0.5 ng/ml for PS, and 2.0 +/- 0.6 ng/ml for PA. Mononuclear cells separated after contaminated dialysis will all types of dialysers expressed increased mRNA levels for IL-1 beta and IL-1Ra. Production of IL-1Ra by cells separated after contaminated dialysis was determined after Cup and PS dialysis; there was increased production of IL-1Ra by these cells (Cup, 10.3 +/- 4.2; PS, 7.3 +/- 2.5 ng/ml) compared to cells separated after sterile dialysis (Cup, 5.6 +/- 2.1, P < 0.05; PS, 4.5 +/- 1.1 ng/ml, n.s.) or from non-circulated blood (Cup experiments, 4.7 +/- 1.5, P < 0.05; PS experiments, 4.1 +/- 1.2 ng/ml, n.s.). CONCLUSIONS: These data suggest penetration of cytokine-inducing substances through both cellulosic and synthetic dialysers. Differences between dialysers may exist regarding extent and time course of penetration. The detection of cytokine mRNA as well as the measurement of IL-1Ra synthesis is a more sensitive marker for the transfer of cytokine-inducing substances through dialyser membranes than the measurement of IL-1 beta protein synthesis.

Advanced glycation end-products in the peritoneal fluid and in the peritoneal membrane of continuous ambulant peritoneal dialysis patients.

In patients on continuous ambulant peritoneal dialysis (CAPD) treatment, the peritoneal membrane is continuously exposed to the high glucose concentration contained in the dialysate. This may lead to the local generation of advanced glycation end-products (AGEs). To test this hypothesis we evaluated the plasma and dialysate AGE concentrations in five CAPD patients. The dialysate was measured after a 1 h and after a 12 h dwell time. Additionally, in two patients an immunohistochemical investigation of the peritoneal membrane for AGE was performed. For the determination of AGE an ELISA using a polyclonal antibody against AGE bovine serum albumin was used; the immunohistochemical staining was performed using the streptavidin-biotin complex method. We found only low concentrations of AGE in the dialysate after a 1 h dwell time; after 12 h, however, the dialysate AGE was even greater than the plasma concentration. In both peritoneal specimens we found positive staining for AGE in the interstitium of the mesothelial layer. The dialysate AGE contained a high proportion of high-molecular-weight AGE proteins and low-molecular-weight AGE was found to be in the same concentration range as the total serum AGE. We conclude that there is local generation of AGE in the peritoneal membrane and a 'washing out' of AGE from the peritoneal membrane during longer dwell times. We speculate that the accumulation of AGE might lead to some of the functional and morphological alterations observed after long-term CAPD.

Pyruvate neutralizes peritoneal dialysate cytotoxicity: maintained integrity and proliferation of cultured human mesothelial cells.

Toxic effects of commercially available peritoneal dialysate (PD) fluid include damage to mesothelial cells (MC), causing a severely disturbed proliferation of cultured MC. We investigated the injury to the cell membrane (by release of lactate dehydrogenase, LDH), the proliferation (by cell counts and by 3H-thymidine incorporation), and optional the cytokine generation (by IL-1 receptor-antagonist production, IL-1 ra) of cultured human MC during the 48 hours after a 30 minute exposure to PD containing either 35 mmol/liter sodium lactate or sodium pyruvate. All solutions had a pH of 5.2 to 5.6 and were composed as standard PD. Glucose contents of 1.36 and 3.86 mmol/liter were tested. After exposure to the lactate-PD containing 1.36% glucose, LDH activity was increased by more than 30%, proliferation of MC was inhibited by more than 30%, and IL-1 ra production was reduced significantly when compared to pyruvate-PD and the control solution. After preincubation with 3.86% glucose containing PD, all negative effects became even more pronounced in the lactate group whereas the MC maintained their integrity, rate of proliferation and IL-1 ra release after pre-exposure to pyruvate containing PD. These results suggest that the acute toxic effects of commercially available PD on the integrity, proliferation and IL-1 ra production of MC can be avoided by the use of sodium pyruvate instead of sodium lactate.

Pyruvate anions neutralize peritoneal dialysate cytotoxicity.

A new peritoneal dialysate containing pyruvate anions was developed in order to avoid cytotoxic effect of conventional lactate-based dialysate. The dialysate has a final pH of 5.4 to 5.6 and is composed of 1.36-3.86% glucose-monohydrate; 132 mmol/l sodium; 1.75 mmol/l calcium; 0.75 mmol/l magnesium; 102 mmol/l chloride and 35 mmol/l pyruvate. For cytotoxicity testing peritoneal macrophages, and mesothelial cells (MC) were exposed to conventional lactate dialysate, and pyruvate dialysate. We investigated the O2- generation and cytokine synthesis after endotoxin stimulation in peritoneal macrophages and the proliferation of mesothelial cells of cultured human MC. After exposure to lactate dialysate O2- generation and cytokine synthesis in peritoneal macrophages and proliferation of mesothelial cells were inhibited when compared to solution containing pyruvate and the control solution. After preincubation with 3.86% glucose containing solutions, all negative effects became even more pronounced in the lactate group whereas after pre-exposure to pyruvate containing solution the toxic effects were absent. These results suggest that the acute toxic effects of commercially available peritoneal dialysates can be avoided by the use of sodium pyruvate instead of sodium lactate.

The role of plasma coating on the permeation of cytokine-inducing substances through dialyser membranes.

We studied the effects of coating of dialyser membranes with plasma proteins on the permeation of bacteria-derived cytokine-inducing substances (CIS). An in vitro dialysis circuit using polysulphone (PS) or modified cellulose triacetate (mCT) dialysers was used. Precoating of the dialysers was performed by recirculation of 10% normal human plasma for 30 min in the blood compartment and subsequent rinse with pyrogen-free saline. Samples from the blood compartment were tested for induction of interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta) and tumour necrosis factor (TNF alpha) at various time points after challenging the dialysate with sterile culture supernatants from Pseudomonas aeruginosa. Contamination of the dialysate resulted in the appearance of CIS in the blood compartment of both polysuphone modified cellulose triacetate (IL-1 alpha: PS, time 0: 81 +/- 11 pg/ml, time 60 min: 4747 +/- 1822 pg/ml, P < 0.05; mCT, time 0: 235 +/- 141 pg/ml, time 60 min: 1632 +/- 531 pg/ml, P < 0.05). The plasma protein layer reduced the penetration of CIS significantly only for polysulphone (IL-1 alpha: PS, time 60: 4747 +/- 1822 versus 880 +/- 525 pg/ml, P < 0.05; modified cellulose triacetate, time 60 min: 1632 +/- 531 pg/ml versus 930 +/- 326 pg/ml). Samples from the blood compartment contained < 6 pg/ml LAL-reactive material at all time points. We conclude that plasma coating of polysulphone dialysers reduces the permeability for CIS derived from Pseudomonas, either by reducing the effective pore size or by adsorption of proteins that bind CIS.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of dialyser membranes on extracellular and intracellular granulocyte and monocyte activation in ex vivo pyrogen-free conditions.

This study examined effects of blood-contacting materials on the monocyte reaction following the first contact of human blood with hollow fibre dialyser membranes under pyrogen-free conditions. Membrane materials were the unchanged regenerated cellulose, the synthetic polysulphone (PS), a positively charged diethylaminoethyl cellulose (DEAE-C), the negatively charged carboxymethyl cellulose (CMC) and acrylonitrile copolymer (AN). The experimental system involved perfusion with human fresh venous blood through different modules containing the materials in the form of hollow fibre membranes. Extracellular and intracellular aspects of blood reactions after the first contact with the materials were investigated in Ficoll-separated granulocytes and peripheral blood mononuclear cells. Investigations were done by release reactions of platelet activating factor (PAF), oxygen radical (O2-), leukotriene B4, prostaglandin E2 (PGE2) and cytokines (IL-1 beta, TNF-alpha, IL-6). The intracellular activation of peripheral blood mononuclear cells was done by mRNA transcription of IL-1 beta, TNF-alpha, IL-6, IL-8 and beta 2-microglobulin (beta 2-MG). From the set of parameters, release reactions were only measurable for PAF, PGE2 and O2- if a second stimulus (phorbol myristate acetate, lipopolysaccharide, zymosan and calcium ionophore) was used after blood-membrane interaction. Although the extent of the release reaction was weak, negatively charged membranes were, in general, more active. All dialysers exhibited the same increase in beta 2-MG mRNA transcription, suggesting that all blood-contacting membranes initiate the gene expression of beta 2-MG at the same level. TNF-alpha, IL-6, IL-1 beta and IL-8 mRNAs were demonstrated in the AN and CMC membranes rather than the other materials, which exhibit a lower transcription than the tubing set. As has been found, an enhanced generation of PGE2 for both CMC and AN membranes supports, therefore, the concept of an effect of the negative charges of the materials in the gene expression of cytokines. However, this initiation does not lead to the generation of cytokines, even after stimulation with pyrogens.

Leukotriene release from neutrophils of patients on hemodialysis with cellulose membranes.

The role of cytokines in patients with chronic renal failure is currently under investigation. We therefore studied the release of leukotriene B4 (LTB4) from polymorphonuclear leukocytes (PMN) in stable dialysis patients treated with two different cellulose membranes, Cuprophan and Hemophan, a modified cellulose with less complement activation. Six patients were treated for four weeks with Cuprophan then switched to Hemophan for another four weeks. Before and after the last treatment of each period, PMN were separated from 20 ml heparinized blood by FICOLL density gradient centrifugation. Portions of 5 x 10(6) PMN were resuspended in Hanks' buffer and stimulated for 5 minutes with calcium ionophore A23187 (5 micrograms/ml). LTB4 in cell supernatants was determined by specific radioimmunoassay. PMN from dialysis patients before HD released significantly (p less than 0.01) more LTB4 than healthy donors. No significant difference between pre- and post-dialysis values was observed with Cuprophan or Hemophan dialyzers. Our data suggest that the acute effects of blood membrane interaction with either complement activating or non-activating dialyzers do not lead to changes in post-dialysis leukotriene metabolism, but leukotriene production is enhanced chronically in dialysis patients.

Leukotriene release from peripheral and peritoneal leukocytes following exposure to peritoneal dialysis solutions.

During continuous ambulatory peritoneal dialysis (CAPD), peritoneal host defence mechanisms are repeatedly exposed to dialysis solutions (with unphysiological composition) which may compromise peritoneal immune cell functions. In this context, the current study focused on the capacity of peripheral and peritoneal PMN to release leukotrienes following exposure to conventional CAPD dialysates. PMN were obtained from peripheral blood of healthy volunteers and from the peritoneal effluent of CAPD patients with acute peritonitis. Following isolation, cells were incubated in fresh CAPD dialysates or control buffer, and calcium ionophore A23187-stimulated leukotriene synthesis was measured. Additional experiments included RP-HPLC analysis and radioactivity monitoring of lipoxygenase products in PMN labelled with 14C-arachidonic acid. Leukotriene B4 and leukotrienes C4/D4/E4 were determined by radioimmunoassay. Ionophore-triggered leukotriene release from cells exposed to control buffer was pronounced in inflammatory peritoneal PMN (70.4 +/- 31.3 ng/5 x 10(6) cells LTB4 and 13.4 +/- 19.8 ng/5 x 10(6) cells LTC4/D4/E4, mean +/- SD, n = 14) when compared to healthy peripheral PMN (26.6 +/- 16.9 ng/ml LTB4 and 6.3 +/- 6.6 ng/ml LTC4/D4/E4, n = 12). Incubation in fresh solutions for peritoneal dialysis severely depressed leukotriene release from both cell populations. These results indicate a severe inhibition of cellular responsiveness as a consequence of dialysate exposure which could contribute to the impairment of host defence early in the CAPD cycle.

Leukotriene B4 and tumor necrosis factor release from leukocytes: effect of peritoneal dialysate.

The effect of peritoneal dialysate on the capacity of peripheral blood polymorphonuclear (PMNL) and mononuclear leukocytes (MNC) to release leukotriene B4 (LTB4) and tumor necrosis factor alpha (TNF alpha) was investigated in vitro. Following density gradient separation, aliquots of 5 x 10(6) PMNL or MNC were incubated in peritoneal dialysis fluid containing 1.5% glucose or Hanks' buffer (= control) for 1-2 h at 37 degrees C. TNF alpha and LTB4 production was stimulated with Escherichia coli lipopolysaccharide (LPS) and calcium ionophore A23187, respectively. MNC incubated in buffer and LPS produced (mean +/- SD) 1,006 +/- 522 pg TNF alpha/5 x 10(6) cells; no significant amounts of TNF alpha were detectable in the presence of dialysate. An inhibition of TNF alpha release was also observed in MNC exposed to bicarbonate-buffered dialysates (pH 7.40) and 4.25% and 1.5% glucose solution with physiologic osmolality. Incubation of PMNL in Hanks' buffer followed by A23187 stimulation led to production of 29.1 +/- 19.2 ng LTB4/5 x 10(6) cells, whereas glucose-incubated cells were refractory to ionophore stimulation (less than 0.1 ng LTB4/5 x 10(6) cells). The failure of dialysate-exposed leukocytes to release inflammatory mediators in response to adequate stimuli may contribute to the impairment of cellular host defense in the setting of continuous ambulatory peritoneal dialysis.

Eicosanoid release as laboratory indicator of biocompatibility.

Biocompatibility evaluation of extracorporeal devices requires the establishment of sensitive indicators of blood cells/surface interactions. Among others, arachidonic acid derivatives, such as prostaglandins and thromboxanes, play an important role in the cell control systems. Hence, the release of eicosanoids during blood exposure to dialyzer membranes was investigated. Experiments included in vitro incubation of human blood with flat membranes (FM), as well as ex vivo perfusion of hollow fiber membranes (HFM) with blood from healthy volunteers in single-pass fashion. In both models, a significant release of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) was detected. In addition, the amount of eicosanoid release depended on the type of membrane tested. After a 10-min FM incubation with fresh blood, plasma concentrations of TXB2 and PGE2 were pronounced by polycarbonate when compared to Cuprophan and polyacrylonitrile. During 10 min of open loop perfusion of HFM, polymethylmethacrylate was the most active biomaterial, whereas the reactivity of Cuprophan was significantly lower. Among HFM, Hemophan was by far the less active. These results indicate that the release of eicosanoids represents a sensitive parameter of blood cells/membrane reactivity. Thus, the question arises as to whether or not the extracorporeal process of cyclooxygenase activity could contribute to the clinical side effects of chronical hemodialysis.