Acute Anaphylactoid Reactions During Hemodialysis in France

A retrospective survey of anaphylactoid reactions during dialysis in France was conducted. In 52 of 112 hemodialysis units surveyed 111 patients who had suffered one or more anaphylactoid reactions during dialysis were identified. According to the Hamilton/Adkinson classification, in 31 patients reactions were minor, in 54 patients moderate, and in 26 patients severe. Four patients died of their reactions. A preponderance of reactions (75 and 11%) occurred with cuprammonium cellulose hollow-fiber and plate dialyzers, respectively. Severe dialyzer reactions were found to occur more frequently after the long (weekend) interdialytic interval. In an in vitro study, six brands of cuprammonium cellulose hollow-fiber dialyzers were rinsed with water and the eluates analyzed by size exclusion chromatography for contaminant particles. Substantial variation in the amount of extractable material was found between dialyzers of different brands, despite the fact that all dialyzers used membranes from the same manufacturer. Previous data by others has suggested that this extractable material is a derivative of cellulose. Results of our epidemiologic survey in France are similar to those previously reported in the United States and suggest an increased incidence of dialyzer reactions with ethylene oxide-sterilized cuprammonium cellulose dialyzers. The presence of cellulose-derived particles in the rinsing fluid of such dialyzers and the possible increased incidence of reactions after the long (weekend) interdialytic interval suggest that allergy to cellulose-derived particles eluted from cellulosic dialyzers may contribute to dialyzer hypersensitivity reactions.     

Dialyzer Reuse Following Manual Reprocessing with a New Sterilant, RenNew-D

Dialysis patients are at risk for toxicity from formaldehyde used in the reprocessing of dialyzers for reuse; therefore, replacing formaldehyde as a dialyzer sterilant would be advantageous. The potential for RenNew-D as a sterilizing agent was investigated in seven stable in-center hemodialysis patients over 20 consecutive dialyses with cuprammonium cellulose hollow-fiber dialyzers. Treatment with RenNew-D showed no toxicity to patients or dialyzers except for two blood leaks occurring in one patient. The mean number of dialyzer uses was 4.9. In all the dialyzers that passed functional testing small solute clearances were maintained with reuse. The ability of RenNew-D to improve the biocompatibility of reused dialyzers was documented with mean neutrophil counts falling to only 78% of initial values during first reuse of dialyzers processed with RenNew-D compared with a decrease in neutrophil count to 2% of initial values during first use of the same dialyzers. Our results suggest that RenNew-D may be a useful alternative to formaldehyde for the purpose of dialyzer reuse. A reuse procedure that includes processing with RenNew-D is associated with improved biocompatibility, possibly because of maintenance of the blood-derived membrane coating established during prior dialysis.     

Effect of dialyzer geometry on granulocyte and complement activation

During hemodialysis with cuprophan membranes, the complement system as well as leukocytes become activated. In order to clarify the role of dialyzer geometry, the effect of hollow-fiber versus flat-sheet dialyzers and of different surface areas on C3a generation and leukocyte degranulation was investigated. Plasma levels of leukocyte elastase in complex with alpha 1-proteinase inhibitor were significantly increased after 1 h (+55%) and 3 h (+62%) of hemodialysis with flat-sheet dialyzers as compared to hollow-fiber devices. In addition, plasma levels of lactoferrin, released from the specific granules of leukocytes during activation, were significantly higher (+42%) 3 h after the onset of dialysis treatment with flat-sheet than with hollow-fiber dialyzers. With respect to surface area, larger dialyzers tended to cause more release of leukocyte elastase as compared to dialyzers with smaller surface areas, irrespectively of the configuration of the dialyzer used. On the other hand, activation of the complement system, as measured by the generation of C3a-desarg, did not differ with both types of configurations. The same held true for leukopenia, which was almost identical for hollow-fiber and flat-sheet dialyzers. From these findings two lines of evidence emerge: First, not only the type of membrane material used in a dialyzer may influence its biocompatibility, but the geometry of the extracorporeal device also determines the degree of compatibility. Hence, the extent of leukocyte activation correlated with both configuration of the dialyzer and surface area of the membrane.(ABSTRACT TRUNCATED AT 250 WORDS)     

Beta 2-microglobulin kinetics in maintenance hemodialysis: a comparison of conventional and high-flux dialyzers and the effects of dialyzer reuse

beta 2-Microglobulin (beta 2M) forms synovial and bony amyloid deposits in long-term hemodialysis patients. To define the kinetics of beta 2M during hemodialysis and the effects of dialyzer reprocessing, we measured serum beta 2M, plasma C3a, and neutrophil counts immediately predialysis; 15, 90, and 180 minutes after beginning dialysis; and 15 minutes postdialysis in ten chronic hemodialysis patients. The studies were performed during first and third uses of cuprammonium rayon and polysulfone dialyzers processed by rinsing with water, then bleach, in an automated system (Seratronics DRS 4) and then packed in 1.5% formaldehyde. Mean serum beta 2M (corrected for ultrafiltration) decreased by 16.6% +/- 18.1% with new cuprammonium dialyzers and 57.1% +/- 12.8% with new polysulfone dialyzers. Dialyzer reprocessing had no significant effect on this decline. Predialysis serum beta 2M decreased by 30.4% +/- 15.5% 1 month after switching from cuprammonium to polysulfone dialyzers; these levels remained stable after 3 months of dialysis with polysulfone. Complement activation and neutropenia during dialysis were significantly more marked with cuprammonium, but were not affected by reprocessing of either dialyzer. In vitro adsorption of 124I-beta 2M to polysulfone fibers was greater than to cuprammonium; adsorption was not influenced by dialyzer reprocessing.     

Role of Dialyzer Contaminants in the Allergic Epiphenomena of Hemodialysis

Abstract: Cuprophan hollow-fiber dialyzers contain contaminants including 1,2,3-propanetriol, carbohydrates, Limulus amebocyte lysate-reactive material, and particulates. In a clinical study, the role of these substances in the allergic-type response seen in some hemodialysis patients was examined. Patients were dialyzed three times per week for 6-week intervals with each of four dialyzer preparations designed to vary the burden of contaminants presented to the patient. Predialysis eosinophil counts and serum immunoglobulin (Ig) E levels were obtained weekly. White cell and platelet counts and plasma C3a and C5a levels were measured during dialysis for each dialyzer preparation. Dialyzer preparation had no effect on predialysis eosinophil counts or IgE levels. All patients demonstrated transient leukopenia and complement activation during dialysis, the magnitudes of which were unaffected by the type of dialyzer preparation. At the levels found in the dialyzers studied, it was questioned whether water-soluble extractables or particulates play any role in the allergic epiphenomena of hemodialysis.     

Dialyzer Performance in the Clinic: Comparison of Six Low-Flux Membranes

The aim of this study is to assess the clinical performance of 6 different low-flux dialysis membranes under steady-state conditions in terms of urea and phosphate clearances. Ten stable hemodialysis patients were examined. The following dialyzers were studied, all in 1.5- to 1.6-m2 format: cuprammonium, cellulose acetate, cellulose diacetate, hemophane, polysulfone (low-flux), and polysynthane. The following parameters were examined: urea reduction ratio, phosphate reduction ratio, "instantaneous dialyzer clearance" for urea and phosphate, and total amount of urea and phosphate removed in the dialysate over a 1-week (three dialyses) period. Although there were differences between the membranes, all produced results within a narrow range. There was no one membrane that produced superior clearances in all categories. The cellulose acetate membrane was the least satisfactory membrane. Phosphate clearances were at best one third that of urea clearances. When choosing a low-flux dialysis membrane, urea and phosphate clearances are so similar amongst different membranes that other criteria are likely to have a greater influence on the choice of membrane.     

Summary

This article discusses the first five Reports presented at the Symposium, those of Drs. Villarroel, Chenowith, Pearson and colleagues, and Henne and colleagues (two presentations). Although Dr. Villarroel Reported hypersensitivity reactions only during hollow-fiber dialysis, this may have been due to the way the information was gathered rather than accurately reflect actual happenings. The Report of the largest number of cases, to date, originated in England and came from a center that used mostly plate dialyzers. Thus, it is probable that any dialyzer may cause the syndrome, although more severe ones may be much more common in hollow-fiber dialyzers. Dr. Chenoweth observed that different membranes activate complement to differing extents but that all cellulosic membranes activate complement. Currently every patient experiences complement activation and neutropenia early in dialysis. It seems unlikely that a biological phenomenon that occurs in almost all dialyses is responsible for a reaction that occurs only in 35 of every 1,000,000 dialyses. Dr. Pearson and co-workers Reported the presence of Limulus amebocyte lysate-reactive material (LAL-RM) in 15 dialyzers tested with three different lysates. All dialyzers with cellulose-based membranes had positive tests with some, but not all, lysate reagents. Second, cell response tests indicative of pyrogenicity in humans were negative. At least two substances could be eluted from hollow-fiber dialyzers. One had a molecular weight of 23,000, the other of 3,100. Both could be inactivated by cellulase. These findings suggest that the LAL-RM is not an endotoxin. As the entire blood path of the dialyzer was rinsed, it is not possible to conclude whether or not the origin of LAL-RM is the headers, casings, or actual fibers. Drs. Henne, Schulze, and co-workers came to the same conclusion as Dr. Pearson; LAL-RM is of cellulosic origin, not an endotoxin. However, in a review of the composition of cotton fiber, the starting material for many dialysis membranes, it is of interest to note that it contains 1.5% protein and 0.6% wax. Perhaps these compounds should be investigated as possible causes of the severe allergic reaction in the rare patient who has it. Drs. Henne, Dietrich, and co-workers Reported on the difficulty of removing ethylene oxide from dialyzers. There are two first-order removal curves. One is for the fibers from which ethylene oxide washes out easily. The second is for the headers and casing. Ethylene oxide seems to be more firmly held in the latter; however much time is spent removing it, ethylene oxide will still leach out during the entire dialysis process. It is difficult to explain “first use syndrome“ allergic reaction by ethylene oxide hypersensitivity. If ethylene oxide were the common cause, one would expect the peak of reactions to occur after the patient had already been sensitized by previous blood transfusions and/or by ethylene oxide-cleaned equipment. Eosinophilia may be associated with the use of ethylene oxide. However, this symptom is not unique to first use syndrome but is a chronic problem with dialysis patients. Perhaps ethylene oxide is a cause of dialysis eosinophilia. This would explain why, in this author's experience, it is more common in hemodialysis patients, followed by continuous peritoneal dialysis (CCPD) patients, and finally by continuous ambulatory peritoneal dialysis patients, since the hemodialyzer exposes the patient to more ethylene oxide than in the tubing used in CCPD.     

Effect of dialyzer reprocessing with Renalin on serum beta-2-microglobulin and complement activation in hemodialysis patients.

The peracetic acid-based sterilant Renalin is increasingly being used for reprocessing hemodialyzers. In order to evaluate the effects of reprocessing on beta 2-microglobulin (beta 2M) kinetics and complement activation in chronic hemodialysis patients, we compared 4 dialyzer membranes on 1st, 2nd and 4th use of the membrane. Dialysis with new cuprammonium rayon dialyzers (0.8 m2) for 4 h resulted in a nonsignificant increase in serum beta 2M concentrations of 10.7% (corrected for changes in extracellular volume) and significant generation of the complement component C3a des Arg. On reuse, minimal changes in serum beta 2M levels were noted and complement activation was absent. Dialysis with new cellulose acetate (CA, 1.5 m2), polyacrylonitrile (AN69 HF, 1.6 m2) or polymethylmethacrylate (PMMA, 1.6 m2) membranes resulted in significant decreases in serum beta 2M levels (19.5, 31.7 and 50.8%, respectively). Reprocessing had negligible effects on the removal of beta 2M by CA and AN69, but by the 4th use halved the effectiveness of PMMA. Reprocessing reduced the significant generation of C3a des Arg observed with new CA and PMMA membranes. We conclude that, except for PMMA, Renalin reprocessing has minor effects on the ability of the membranes to remove beta 2M and improves the biocompatibility of all membranes studied.     

Residual Formaldehyde in Dialyzers: Quantity, Location, and the Effect of Different Methods of Rinsing

When formalin-sterilized dialyzers were rinsed by our standard technique (similar to that used in many other dialysis centres) undesirable concentrations of formaldehyde were found in the dialyzers at the start of dialysis. When the technique was modified by passing part of the saline through the blood compartment immediately before connection and discarding the saline left in the dialyzer at the time of connection, the concentration of formaldehyde infused into the patient fell below 2 μg/ml. However, the dialyzers still contained up to 13 mg of formaldehyde which leached slowly from the dialyzer during simulated dialysis. Some residual formaldehyde was found in several components of the dialyzer but the great majority was contained in the cellulose membrane.     

Complement Activation During Hemodialysis: Laboratory Evaluation of Hemodialyzers

A laboratory method that facilitates delineation of the complement-activating characteristics of various dialyzers under defined conditions has been developed. Results obtained by circulating reconstituted human serum through these devices and measuring time-dependent production of both C3a and C5a antigens are entirely consistent with previous clinical observations. For example, the complement-activating potential of dialyzer membranes could be described as high (cuprammonium cellulose), moderate (cellulose acetate), or low (polycarbonate or polyacrylonitrile). Furthermore, these techniques provided the opportunity to identify membrane characteristics that are not readily defined by clinical studies alone. Specifically, membranes that transported and absorbed C5a antigen were readily identified by these methods. Additionally, laboratory evaluation provided the unique ability to define the efficiency of complement activation taking place on the membrane surface. Results of these investigations are compatible with a hypothetical model that not only describes the properties of a typical dialyzer membrane but may be generally applicable to other biomaterials as well.     

Multiple use of dialyzers: safety and efficacy

The practice of multiple use of dialyzers was examined over a 15-month period on all 104 patients in a chronic maintenance hemodialysis facility. A computerized medical information system permitted analysis of the incidence of events in over 10,000 successive hemodialyses. It also allowed analysis of the events in 27 patients dialyzed for a total of 655 months successively in two units practicing single and multiple dialyzer use. The incidence of complications during dialysis, of complications that might be related to infection, and the rate of hospitalization was not greater when the 27 patients were dialyzed in the unit practicing multiple use as compared with the rates in the unit practicing single use. Events possibly associated with infection did not occur more frequently during dialyses in which the dialyzer had been used between 2 and 20 times than they did with the initial use of the dialyzer. With successive dialyzer use, there was no significant change in the ability to remove fluid or in the dialysance of urea and creatinine. The neutropenia that characteristically occurs early in dialysis was substantially less with reused dialyzers than with their initial use. Under the operating conditions described, we conclude that multiple dialyzer use over a 15-month period is safe, efficacious, and is not associated with an increased rate of infection, of morbidity from any cause, or of mortality.     

Ethylene Oxide in Dialyzer Rinsing Fluid: Effect of Rinsing Technique, Dialyzer Storage Time, and Potting Compound

Ethylene oxide (ETO) is recognized as one of the main causes of dialyzer-associated hypersensitivity reactions. We studied the amount of ETO in the rinsing fluid of ETO-sterilized hollow-fiber dialyzers as a function of rinsing technique, dialyzer storage time, and the amount of potting compound (known to be an ETO reservoir) in the dialyzer. The results suggested that the initial 500 ml of rinsing fluid removes much of the residual ETO in the dialyzer. Ethylene oxide extraction was enhanced substantially by rinsing at 37 degrees C versus 5 degrees C. However, considerable amounts of ETO remained in the dialyzer after an initial 500 ml rinse, some of which could be removed by rinsing with an additional 1,500 ml. High concentrations of ETO were measured in fluid that had been recirculated through the dialyzer for 10 min or longer and in fluid that had been allowed to remain in the dialyzer for 10 min under zero-flow conditions. The amount of ETO in the rinsing fluid decreased markedly as the dialyzer storage time was increased from 4 to 8 weeks and in dialyzers in which a portion of the potting compound had been replaced with a polycarbonate ring. Our results suggest that the dose of ETO administered to the patient at the outset of dialysis can be minimized by rinsing the dialyzer with 2 L of fluid at 37 degrees C and by avoiding administration of rinsing fluid that has been allowed to remain in contact with the dialyzer for more than several minutes. Use of a long storage interval and use of dialyzers containing reduced amounts of potting material will also reduce the ETO load.     

Effect of Dialyzer Reprocessing Methods on Complement Activation and Hemodialyzer-Related Symptoms

The effects of different dialyzer processing methods and of reuse on complement activation and dialyzer-related symptoms were studied in 96 maintenance hemodialysis patients. New dialyzers were either unprocessed (Group 1) or machine-washed with bleach and stored in formaldehyde (Group 2). Reused dialyzers were manually cleansed using the combination of bleach and formaldehyde (Group 3), or machine-washed in formaldehyde (Group 4) or peracetic acid (Group 5). Prewashed new dialyzers (Group 2) were associated with greater complement activation during dialysis when compared with unprocessed, new dialyzers (Group 1) (p less than 0.05). Reused, unbleached but formaldehyde-treated or peracetic acid-treated dialyzers (Groups 4 and 5) were associated with reduced complement activation (p less than 0.05). Complement activation was not reduced when bleach was used for reprocessing (Group 3). The percentage of patients without symptoms during dialysis was significantly greater with reused dialyzers than with new dialyzers (Groups 3 through 5 versus Groups 1 and 2; 39 versus 25%; p = 0.035). The severity of total symptoms correlated significantly (p = 0.0004) with complement activation. Our results suggest that total symptoms during dialysis are correlated with the degree of complement activation. However, trends in the data pertaining to chest pain suggest that factors other than complement activation may be important in the pathogenesis of some dialyzer-related symptoms.     

Computational Evaluation of Dialysis Fluid Flow in Dialyzers With Variously Designed Jackets

Dialyzer performance strongly depends on the flow of blood and dialysis fluid as well as membrane performance. It is necessary, particularly to optimize dialysis fluid flow, to develop a highly efficient dialyzer. The objective of the present study is to evaluate by computational analysis the effects of dialyzer jacket baffle structure, taper angle, and taper length on dialysis fluid flow. We modeled 10 dialyzers of varying baffle angles (0, 30, 120, 240, and 360°) with and without tapers. We also modeled 30 dialyzers of varying taper lengths (0, 12.5, 25.0, and 50.0 mm) and angles (0, 2, 4, and 6°) based on technical data of APS-SA dialyzers having varying surface areas of 0.8, 1.5, and 2.5 m² (Rexeed). Dialysis fluid flow velocity was calculated by the finite element method. The taper part was divided into 10 sections of varying fluid resistances. A pressure of 0 Pa was set at the dialysis fluid outlet, and a dialysis fluid flow rate of 500 mL/min at the dialysis fluid inlet. Water was used as the dialysis fluid in the computational analysis. Results for dialysis fluid flow velocity of the modeled dialyzers indicate that taper design and a fully surrounded baffle are important in making the dialysis fluid flow into a hollow-fiber bundle easily and uniformly. However, dialysis fluid flow channeling occurred particularly at the outflowing part with dialyzers having larger taper lengths and angles. Optimum design of dialysis jacket structure is essential to optimizing dialysis fluid flow and to increasing dialyzer performance.     

Plasma levels of main granulocyte components in patients dialyzed with polycarbonate and cuprophan membranes

Plasma levels of granulocyte lactoferrin, granulocyte myeloperoxidase and granulocyte elastase in complex with alpha 1-proteinase inhibitor (E-alpha 1PI) were investigated in regular hemodialysis patients dialyzed with hollow-fiber dialyzers made from polycarbonate (FD 100) or cuprophan (GFS 120 H). Plasma levels of all these main granulocyte components increased significantly during hemodialysis. E-alpha 1PI levels were significantly higher in patients dialyzed with the polycarbonate compared with the cuprophan membrane, whereas the increases of myeloperoxidase and lactoferrin were not different for the two dialyzers. On the other hand, plasma C3a levels were higher in patients dialyzed with the cuprophan compared with the polycarbonate dialyzer. Therefore, granulocyte activation during hemodialysis does not necessarily need complement activation.     

Relationship between dialyzer reuse and the presence of anti-N-like antibodies in chronic hemodialysis patients.

One hundred eleven chronic hemodialysis patients from five dialysis units were tested for the presence of antibodies reactive with red blood cell N substance; 77 patients were available for follow-up study after 18 to 24 months. Initially, 18 patients (16%) had serum anti-N-like antibodies. Thirteen of these patients were in a home dialysis program and were reusing hollow fiber dialyzers. The other five had practiced hollow fiber dialyzer reuse in the past. None of 37 patients using coil dialyzers had anti-N-like antibody. On follow-up testing, anti-N-like antibody persisted in all patients restudied except for one who had a successful renal transplant. Anti-N-like antibodies developed in four additional patients: three were reusing hollow fiber dialyzers at the time, but one had not reused dialyzers for 24 months. Statistical analyses indicated that dialyzer reuse, hollow fiber dialyzers, and home dialysis were significantly related to the presence of anti-N-like antibodies. We interpret the clinical and statistical data to indicate that dialyzer reuse is the major clinical factor in the development of anti-N-like antibody. The likely mechanism involves the prolonged exposure of red cells trapped in the dialyzer to formaldehyde used in preparing dialyzers for reuse. No adverse clinical effects of anti-N-like antibodies were evident in our patients, but hemolysis and acute transplant failure have been reported by others.     

Evaluation of Three Dry-Sterilized Hollow Fiber Artificial Kidneys

We investigated three new dry sterilized hollow fiber artificial kidneys (HFAK) (Cordis Dow CDAK 1.3, Travenol CF 1200, Extracorporeal Tri-Ex 1). Dry sterilization makes these dialyzers more economical by shortening set-up time. Dry sterilization also eliminates iatrogenic administration of residual sterilant. Water of imbibition can significantly increase the blood compartment volume of the dialyzer during dialysis. Consequently, a corrected blood volume for each dialyzer was established; these corrected volumes varied from 13-36% greater than the volume determined before dialysate flow. With low dose heparinization of these dialyzers there was between an 18 and 45% decrease in the post dialysis volume, presumably due to fiber clotting during dialysis. This volume added to the residual blood loss measured by a colori-metric technique accounted for a possible blood loss ranging between 26.9 and 53.9 ml per dialysis for these three dialyzers. Our results suggest that a relationship between dialyzer clotting and decreased dialyzer efficiency may exist. These three capillary flow dialyzers had a much lower platelet drop (0-9% pre to post) when compared to 30-40% drop of flat plate dialyzers. These dialyzers were found to be safe and easy to use but the high fiber clotting warrants further investigation in chronic dialysis patients on high dose heparin.     

Complement Activation During Hemodialysis: Clinical Observations, Proposed Mechanisms, and Theoretical Implications

Abstract: Human C3a radioimmunoassay techniques were employed to define both the temporal profile and the amount of complement activation taking place in the extracorporeal circuit during maintenance hemodialysis. Prospective studies demonstrated that C3a formation, like hemodialysis-associated leukopenia, was a transient phenomenon that occurred predominantly during the first 30 min of dialysis. Quantitative comparisons revealed that new Cuprophan hemodialyzers displayed somewhat greater complement-activating potential than cellulose acetate dialyzers. By contrast to new Cuprophan membranes, both reused Cuprophan and polyacrylonitrile dialyzers exhibited only a modest ability to activate human complement. These findings are compatible with the known mechanisms of complement activation and suggest that certain chemical and biochemical methods might be exploited to enhance the biocompatibility of cellulose dialysis membranes.     

Differential Effect of Hemodialysis Membranes on Human Lymphocyte Natural Killer Function

Lymphocytes exposed to cuprammonium cellulose membranes have been shown to exhibit depressed natural killer (NK) function. In the present study we investigated the extent to which three dialyzer membranes of different compositions suppressed human lymphocyte NK activity. Peripheral blood lymphocytes or T cells from normal donors were exposed in vitro to cuprammonium cellulose, cellulose acetate, or polycarbonate dialyzer membranes. After exposure to the membranes, NK activity of the cells was studied by using the NK-sensitive cell line K562 as targets. All three membranes adversely affected human lymphocyte NK function, with cuprammonium cellulose producing the most (70-80%) and polycarbonate producing the least (10-15%) suppression. Our results suggest that the composition of dialyzer membranes affects the extent to which the membranes impair human lymphocyte function. The use of more biocompatible membranes might lessen the potential clinical impact of abnormal NK function in hemodialysis patients.