The International Journal of Artificial Organs / Vol. 25 / no. 5, 2002 / pp. 470-479
Biomaterials and their Application
Polymers in nephrology Characteristics and needs J. VIENKEN BioScience Department, Fresenius Medical Care, Bad Homburg - Germany
ABSTRACT: Polymers employed as biomaterials in nephrology serve for different applications: they form membranes for dialysis and plasmapheresis, are used as materials for dialyser housings and as a potting mass for capillary membranes, they make up tubing-systems for extracorporeal circuits and – in the form of beads – act as parts of adsorber columns for hemoperfusion or immunoadsorption. However, generally speaking, many polymers have not yet been designed for their final application. To date, many polymers are still taken from the chemist's shelf according to their alleged performance properties or to their sterilisability. When used in medical application, polymers must show a high purity. Uncontrolled leaching of oligomers from the polymer backbone or of additives from or during the manufacturing process must be avoided. Blood and other body fluids are extremely effective in extracting any loosely bound polymers. During long-term application, e.g. in patients suffering from chronic diseases, these effects may lead to an accumulation of these compounds in circulating blood, tissue, or joints. Consequently, polymers should show an excellent biostability and not degrade during their ageing process. The amount of extractable material should be kept low in order to avoid inflammatory reactions. Polymers must have high blood compatibility in terms of minimized celland complement activation. Polymers for medical application should at best be able to stand high temperatures in order to survive steam sterilisation. If this is impossible, their release kinetics for residual quantities of sterilizing agents should be fast. Finally, protein adsorption should appear under controlled conditions, otherwise a reduced performance through protein adsorption will take place. Further, the uncontrolled activation of biochemical cascades, such as the coagulation, complement or contact phase cascade, following blood/material contact must be minimized. A final aspect has been recently made responsible for adverse patients reactions, the interaction between polymers and medicinal drugs. This drug/material interaction must be low, at best zero, apart form those situations, where a controlled drug-release is wanted. The chemical variety of polymers for medical application is large. However, all typical requirements cannot be met by one single polymer. Compromises have to be found between properties and application. Polymer selection for application in nephrology has always to be made under the premise of final application. (Int J Artif Organs 2002; 25: 470-9) KEY WORDS: Polymers, Dialysis, Residuals, Biocompatibility
0391-3988/470-10 $05.00/0
©
Wichtig Editore, 2002
0391-3988/470-10 $05.00/0
Vienken
INTRODUCTION AND POLYMER SURVEY Hemodialysis with its extracorporeal blood circuit represents the major field of polymer application. Recent development strategies have been to reduce dimensions of the circuit whilst maintaining its performance and blood compatibility. Further efforts have been made to introduce new polymers for the extracorporeal circuit to improve biochemical and biophysical surface characteristics (see also the paper of S. Bowry in this issue). Because all the components of the extracorporeal circuit are in contact with blood, the selection of polymers used in the system is critical. The goal of all biomaterials used in the past was to achieve a suitable combination of physico-chemical properties in order to overcome immunological or allergic reactions following blood/ material contact. Many different polymers have been introduced so far following investigations on implants and prostheses, a realm where more than 40 different polymers were used in the 80s (1). Many years of application have proved the advantages of using the following polymers: Polyvinylchloride (PVC) is used for blood tubings and bags for peritoneal dialysis, Polycarbonate (PC) and Polypropylene (PP) are used in dialyser housings, Polyurethane (PUR) is applied as a potting material for capillary membranes at both ends of the dialyser to separate the blood compartment from the dialysis fluid compartment, silicone rings guarantee that there is no blood leakage between the dialyser housing and its header and finally membrane polymers are typically those materials that are used in the textile industry (Fig. 1). In the early days of dialysis, membranes were made from cellophane, a cellulose nitrate moiety used in the sausage industry. A membrane from the natural polymer cellulose obtained after regenerating cellulose from the solvent Cuoxam (Cuprophan®), (2, 3) soon replaced cellophane and turned out to be the dominating membrane polymer until the end of the 80s, it is now being replaced by modified cellulose (4-7) or synthetic polymers (8-11). Blends of hydrophobic polymers with hydrophilic compounds have turned out to be advantageous for hollow fibre membrane manufacturing in dialysis (12). Typical representatives for polymers used in hemodialysis are those made from the natural polymer cellulose, such as regenerated cellulose (Cuprophan®),
Fig. 1 - Polymers used in extracoporeal circuits include silicones, polyurethane (PUR), polycarbonate (PC), polyvinyl chloride (PVC) and its plasticizers DEHP/MEHP, polyolefines and a series of membrane polymers, which are standardly based on polymers from the textile industry.
modified celluloses (4-7), such as cellulose acetate, benzylcellulose (13) or Vitamin-E-bonded cellulose (14), as well as their synthetic counterparts from polysulfone (PSu) (10), polyacrylonitrile (PAN), polyamide (PA), (8, 11) and polymethylmethacrylate (PMMA). Figure 2 lists the structure of some of the polymers currently available for membrane manufacturing. Polymers for other applications than hemodialysis, such as hemofiltration, plasmapheresis or oxygenation are hydrophobic polyarylethersulfone (PES), polycarbonate, polyamide, polyvinylchloride, modified acrylic acid, polyether, polyurethane, polyacrylonitrile, polypropylene, polyetherimide (PEI) and its copolymers as well as hydrophilic polyvinyl-pyrrolidone (PVP), polyethylene glycol (PEG), polyglycolmonoester, copolymers of glycols, cellulosic derivatives, polysorbate, polyethylene and polypropylene-oxidecopolymers. Polyvinylchloride, the golden standard of polymers for infusion bags and tubing material, has come under attack due to its alleged release of plasticizers and related possible adverse clinical reactions. Investigations published by the US-American Centre for Devices and Radiological Health (15) demonstrate a low risk of these plasticizers (DEHP, MEHP), for dialysis patients. However, it is still an open question whether the longterm release of plasticizers to patients with chronic kidney disease, shown to be in the range of 360 µg
471
Polymers in nephrology
Hemocompatibility
Fig. 2 - Chemical formula of the most widely used membrane polymers for medical application.
DEHP/kgBW/day (15), may still evoke some risks. These risks may be associated to an accumulation in the body due to the failing kidney. Alternatives to PVC base on polyolefines, i.e. blends of polypropylene, polyethylene and others, which do not contain plasticizers. Polycarbonate (PC) as a material for the housing of dialysers and adsorber cartridges is considered to be the classical polymer for this application, despite its considerably high costs. PC shows an advantageous transparency, it is steam-sterilisable and offers a stable rigidity. A modern alternative to PC is polypropylene (PP). PP is sufficiently transparent and dependent on its molecular weight stiff enough to be applied as housing polymer, e.g., the FX-class of dialysers from Fresenius Medical Care, Bad Homburg, Germany, which has been recently introduced to the market uses PP as modern dialyser-housing.
472
Polymers used in nephrology must always be evaluated from the perspective of blood compatibility. It is estimated that if a patient has been undergoing dialysis for 15 years, her/his blood will have come into contact with approximately 4,000 m2 of foreign surface. This is about the size of a football field. Polymer properties have been associated with biocompatibility parameters and possible clinical sequelae over the years. However, although differences could be found for many parameters in vitro, only a few indicators have turned out to be of significant value in the clinical setting (12, 16). This has also been confirmed by ISO 10993, Biological evaluation of medical devices, Part 4, Selection of tests for interactions with blood, which states: “Blood-device interaction is any interaction between blood or any component of blood and a device resulting in effects on the blood, or on any organ or tissue or on the device. Such effects may or may not have any clinical significant or undesirable consequences” (17). The European Society has given a rather pragmatic definition of biocompatibility in this context for Biomaterials: “Biocompatibility is the ability of a material to perform with an appropriate host response in a specific application.” According to this understanding, polymers should not be absolutely inert when applied in medical devices; an appropriate response is even expected, as long as this response is advantageous. Moreover, inert biomaterials (polymers) are not feasible, as was shown by recent mathematical models of coagulation (18) and supported by collective experimental experience. Several hundred publications have been written in the past with an intense description of the hemocompatibility of materials used in dialysis. Many of the related observations and analyses are nicely summarized in a collection of papers from the Consensus Conference on Biocompatibility, published as a supplement issue of Nephrology, Dialysis & Transplantation (19). It is not the scope of this paper to address all polymer-related effects on biocompatibility. I will focus on a selection of biocompatibility parameters that are accepted to ascribe polymer properties to (adverse) clinical reactions.
Vienken
a) Protein adsorption When blood is in contact with artificial surfaces, protein deposition and adsorption occurs. This reaction occurs within milliseconds and affects polymer performance (18). In hemodialysis, the membrane’s filtering capacity must, therefore, be seen under the complex interaction of polymer composition and protein adsorption (20, 21) Protein adsorption depends on the chemical surface characteristics of the polymer (Fig. 3) and on the actual composition of blood. Under this premise, it is possible to approach the polymer's hemocompatibility through a chemical surface modification. However, a particular diet, diseases such as diabetes and uremia, or the administration of drugs, such as erythropoietin (EPO) or aspirin, may change the pattern of protein adsorption. Many hemocompatibility parameters are triggered by the interaction of activated proteins that have been adsorbed at the surface of a polymer. The coagulation cascade, once triggered through the activation of platelets, follows this scheme, as well as the activation of the complement system. It is believed that the deposition of Factor C3b triggered through hydroxyl-groups at the polymer surface, is the initial event. It is possible to control the level of complement activation during hemodialysis through a chemical modification of the polymer or its surface sites (6, 7, 12). The intro-duction of chemical substitutes such as anion-exchanger groups (4, 5), or propionate, butyrate or stearate compounds (6) or carbamate modifications (7), leads to a reduction of complement activation by cellulosic materials. This effect strongly depends on the degree of substitution and thus offers a practical tool for adapting polymers to the needs of the medical community. Protein adsorption should, therefore, be carefully controlled when developing biomaterials for dialysis.
b) Contact phase activation In 1990, Tielemanns et al (22) reported lifethreatening anaphylactoid reactions occurring within the first five minutes of hemodialysis. The authors observed reactions such as oedema of the face, tongue and lips, as well as bronchospasms, hypo-tension, vomiting and abdominal cramps. Tielemanns’ data were later
Fig. 3 - The chemical structure of polymers in medical application determines its blood and tissue compatibility.
Fig. 4 - Physiological cascade describing the underlying mechanism of bradykinin formation (contact phase activation) following blood contact with negatively charged surfaces. These reactions are even amplified by the use of ACE-inhibitors.
supported by a series of publications up to the year 2000 (27) by other authors (23-28). An analysis of the possible mechanism involved is shown in Figure 4. Contact phase activation occurs when blood comes into contact with a variety of negatively charged surfaces, not only in dialysis but also in LDL-apheresis using negatively charged dextran-sulfate beads (29) and after contact with biomaterials (30). The contact phase implies the activation of the intrinsic coagulation, kinin and fibrinolytic systems. The Hagemann factor (Factor XII) is the key to this activation mechanism and once activated, high molecular kininogen and prekallikrein are proteins that are then further activated and thus the contact phase cascade is kept going. Hagemann Factor binding to dialysis membranes strongly depends on their chemical nature and does not depend on the anticoagulant used (31).
473
Polymers in nephrology
During hemodialysis with negatively charged membranes, such as with PAN blended with methallysulfonate (AN69, Hospal, France), the generation of bradykinin in femtomolar concentrations (fmol = 10-15 mol) (26, 28) is triggered. This may lead to severe reactions in sensitive patients (26). Unfortunately, common treatment conditions in dialysis provide a further amplification loop in this cascade. Simultaneously administered angiotensin-converting enzyme inhibitors (ACEi) amplify the above-mentioned reactions (see also Fig. 4). This was the first time that an interaction of medicinal drugs was linked with the specific surface properties of biomaterials. It also proved that these reactions could be overcome through chemical surface modification (28) or the use of uncharged surfaces (28, 30). However, it should be noted that under certain conditions even uncharged materials might be prone to bradykinin formation (32). It is possible that during reprocessing of dialysers (reuse) negative charges are artificially introduced onto a material’s surface. During reprocessing filters for reuse the device has to be rinsed with oxidizing agents, such as hydrogen peroxide, peracetic acid or bleach. This may modify the chemical composition of the protein layer through oxidation and thus create negative charges, e.g., disulfide bridges in proteins are split and the negatively charged cysteinic acid is formed. Similar to the mechanism described above, these negative charges will cause adverse reactions or at least bradykinin formation. In order to avoid these reactions, prerinsing of negatively charged devices with alkaline solutions at a pH of 8.0 is necessary, as recently suggested (33). Most of the literature on adverse reactions based on bradykinin release excluded these effects after contact of blood with polysulfone polymers, because classical PSu-membranes had not been associated with negative charges so far. However, with the advent of new polymer-blended polysulfones, negatively charged PSumembranes are now available on the market. Negative charges can here be detected by using zeta-potential (ζPotential) measurements at different pHs (34). As shown in Figure 5, the presence of acidic surface sites in PSu-membranes depends on the type of polysulfone and its respective manufacturer. The number of acidic surface sites, representing negative charges, is zero for
474
Zeta-Potential of PSu-Membranes Isoelectric Points
Fig. 5 - Polysulfones are not all alike. Classical PSu-membranes don’t bear any negative charges (e.g. PSu-F60, Fresenius Medical Care). Newly developed PSu-membranes may show surface electronegativity, as illustrated by the number of acidic surface sites.
the F60-PSu membrane from Fresenius Medical Care, Germany, whereas the value for the PSu (APS150) made by ASAHI/Japan amounts to 21.2.
Sterilisation issues, biostability and safety Polymers in dialysis are generally used in the longterm. For instance in 1999, the number of patients on chronic hemodialysis in Japan treated for more than 15 years is reported to be >12,500 and the number of patients on dialysis for more than 25 years is shown to be >2000 (35). Long-term treatment suggests the need for high purity devices and components, because patients with end-stage renal disease are unable to effectively excrete toxins originating from extractable materials. Consequently, plasticizers and other leachables from the extracorporeal circuit may then accumulate in the body’s blood or tissue (36). Since recent years, the term “biostability” has become a prominent topic when describing polymer characteristics and their behaviour in practical dialysis. Biostability was then defined as “...the ability of a substance to remain unchanged in a given biological environment” (19). Symptoms based on such an intoxication may slowly develop over weeks or months, leaving the nephrologist with the difficult task of distinguishing between the symptoms caused by the progression of the patient’s
Vienken
Fig. 6 - Gamma-irradiation leads to material degradation in dry cellulosic membranes and gives rise to the presence of compounds with different molecular weights, ranging from below 10,000 to 400,000. Modified from (40).
Fig. 7 - Membrane leachables received after gamma-irradiation are cytotoxic for guinea pig ovary cells, whereby the effects are irradiation-dose dependent. Modified from (41).
basic disease and reactions to toxic substances originating from the extracorporeal system. To illustrate this point, some examples will be given here. Residual and extractable ethylene oxide (ETO) was considered to be the major culprit for the “first-usesyndrome”. This syndrome represents a hypersensitivity reaction observed after first use of hemodialysers and was first described in the late seventies (37, 38). To remove ETO and to cleanse dialysers from any residual material, reprocessing (reuse) of dialysers by rinsing the device with oxidizing agents is practiced mainly in the USA. However, the residual amount of ethylene oxide does not only depend on the rinsing procedure, it is also determined by the chemical nature of polymer. Some polymers may adsorb ETO more than others (PUR, PMMA) and let the gas release with rather slow kinetics. For example, the reduction to one-tenth of its initial ETO-concentration was found to be 24 h for polypropylene and soft PVC, 171 h for hard PVC, 30 60 days for both PUR and polystyrene and 3,5 years for PMMA (39). Such polymers may act as reservoirs for the sterilising gas ETO. If ETO is not properly removed, they may expose sensitive patients to severe risks of adverse reac-tions. The advantage of sterilizing with ETO is the low process temperature. It renders this technology advantageous for many temperature-sensitive polymers. However, an effective degassing of polymers in order to remove residual ETO-amounts must
be a standard manufacturing procedure. Similar arguments hold true for γ-irradiation. High radiation-doses may lead to changes in the polymerstructure and to material degradation. As a consequence, extractable oligomers as well as a reduced tensile strength may occur. Already in 1987, Takesawa et al (40) published the analysis of the molecular weight spectrum of extractable material from cellulosic membranes after gamma-irradiation. According to their findings, gamma-irradiation of dry cellulosic membranes has many deleterious effects: the membrane pore radius is reduced, the membrane’s physical structure is altered, and extractable material of different molecular weights can be detected (Fig. 6). Such leachables can be considered to be cytotoxic for biological cells, as also shown by Bommer et al, (41) for other components of the extracorporeal circuit (Fig. 7), such as PUR (potting materials in dialysers) and PVC (tubing and infusion bags). γ-irradiation may also change the chemical composition of polyurethanes, used as potting material in dialysers. When using aromatic PUR’s, the presence of the carcinogen methylene-di-anilin (MDA) could be detected after γ-irradiation (42, 43). Plasma or body fluids contain electrolytes, a variety of fats, surfactants, nitrogen-based compounds and sometimes even bacteria and fungi. It is easily conceivable that in this aggressive biological environment, polymers may be both subject to surface
475
Polymers in nephrology
erosion associated with leaching of monomers or oligomers and molecular chain disruption following hydrolytic depolymerisation. Implanted polyurethanes, show a reduction in molecular weight after six months’ of subcutaneous implantation (44). An interesting case related to the biostability of polymers in dialysis occurred in September 1996 (45). Seven patients at a hospital in Alabama (Georgia, USA) experienced acute diminished vision and hearing less than 24 hours after hemodialysis with cellulose acetate membranes, which previously had an excellent safety record. It later transpired that the clinic had used dialysers that were more than 10 years old. A detailed analysis of the underlying cause revealed that cellulose acetate undergoes an ageing process (45) associated with a decrease in molecular weight (MW) in relation to its age, from an average MW of 65,000 down to 55,000. De-acetylation was observed in infrared spectra of two dialysers. Polymer chain scissions and oxidation were considered to be the main reason for the reduction in MW. Reactions of this type at ambient temperatures are slow, thus long periods of time are required to allow the de-acetylation products to accumulate. Animal studies performed by the Center for Disease Control and Prevention in Atlanta (Georgia, USA) proved that material released by membranes degraded through chain scission and de-acetylation was most likely to produce some or all of the symptoms observed in patients. The worldwide accepted life-time for sterile disposables kept under suitable conditions is now 2-3 years. Dialysers, tubing and bags should, therefore, not be used after their expiration date. In 1984, Oba et al reported on adverse reactions associated to the eyes of hemodialysis patients (scleritis, iritis). Symptoms occurred after contact of blood with membranes made from cellulose acetate (46). According to these data, blood extracts compounds from dialysis membranes and leaves them in the blood stream. These acetylated derivatives also caused iritis in control experiments in rabbits and hyperemia of the bulbar conjunctiva in dogs. It is interesting to note that the effects were dependent on the year of manufacturing, they were more frequent in 1982 than in 1981. These observations lead us to the conclusion that process parameters during manufacturing need to be carefully controlled and kept
476
constant in order to avoid these adverse events. Recently in 2001, a similar outbreak of syndromes related to cellulose acetate dialysers membranes was reported from Israel (47). This proves show that such adverse events may even happen in our days despite the fact that knowledge about underlying causes exist. The investigations reported here (47) demonstrate that twenty-two of 24 dialysis patients developed a spectrum of symptoms and physical signs including red eyes, hearing loss, tinnitus and bone pain. These adverse events lasted up to six months (tinnitus). Their common denominator was always the first use of a cellulose acetate dialysis membrane (CA 210, Nippro, Japan). Control experiments in rabbits with eluates from these dialysers showed similar effects, paralleled by a significant infiltration of eosinophilic cells into spleen, bone marrow, lung and striated muscle (47). Polymer properties further determine quality control assessments during manufacturing of medical devices in dialysis. This notion is illustrated through the following example: all dialysers have to be checked for blood leaks on a one-by-one basis. A common procedure for leak-tests is to apply a high pressure on the dialysate side of a dialyser (using oxygen or nitrogen) and then to analyze the pressure drop on the lumen side of the capillary membrane. Any blood leak can be demonstrated by the occurrence of gas bubbles. This procedure is simple and works without problems as long as membranes under investigation are hydrophilic and thus, up to a certain threshold value, impermeable for gases. Partially hydrophobic membranes, however, are permeable for the testing gas. Assessment techniques have therefore to be modified in such a way that the membrane is made impermeable for gases prior to the test-procedure, e.g., by the addition of liquids made of perfluorcarbon. Recently, a series of fatal incidences occurred in Croatia and Spain which could be related to the use of perfluorcarbon as a tool for testing blood leaks in dialysers with cellulose acetate membranes (48). According to preliminary investigations, patients have died due to heart embolisms. These reactions were shown in animal trials on dogs already about 25 years ago (49). The underlying mechanism may be described as follows: perfluorcarbon-liquids are standardly used as
Vienken
artificial oxygen carrier, once in contact with athmospheric gases they are loaded with these moieties. An insufficient rinsing of dialysers after the leak test and before final packaging may have let to an increase of residual perfluorcarbon in the membrane bulk. During hemodialysis, this compound saturated with O2 and N2, may have been extracted by blood. Once put into the blood circulation, the gas tension of perfluorcarbon (FC80) and its associated oxygen/nitrogen gases may exceed the total tension of alveolar gases (atmospheric pressure, Henry’s law). As a consequence, the formation of large bubbles made of O2, CO2, N2 and water vapour may have occurred. The application of polymers in nephrology must always be considered under the aspect of a system’s approach. It includes manufacturing processes as well as the final application in the patient.
patients each year, worldwide. Careful observations of changes in the polymer surface following protein deposition, and control of age-related polymer degradation, as well as the correlation of quality-control tests with polymer properties will help to overcome major side-effects. Future developments will focus on drug-polymer interactions as exemplified in unfavorable effects associated with the use of ACE-inhibitors and negatively charged biomaterials. The development of next generation polymers may include positive effects of drug-polymer interactions in terms of a controlled bioactive feedback after blood-material contact. “The future of polymers in dialysis is bright, and possibly limited only by cost pressure in today’s healthcare environment (50).”
CONCLUSIONS Polymers in nephrology represent a success story. Their mechanical stability, surface variability and sterilisability mean that a safe and standardized treatment is possible for more than a million kidney
Reprint requests to: Joerg Vienken, Dr. Ing. BioScience Department Fresenius Medical Care Else Kroenerstrasse 1 D 61342-Bad Homburg, Germany e-mail:
[email protected]
REFERENCES 1. Hench L. Biomaterials. Science 1980; 208: 826-31. 2. Bandel W. Entwicklungen auf dem Cuprophan-Membranund Hohlfaser-Gebiet Mitt. AG für Klin. Nephrologie1975; 4: 29-47. 3. Henne W, Dünweg G, Bandel W. Hollow fibre dialysis membrane. UK-Pat. Appl. GB 2 090 187, 07.07.1982. 4. Baurmeister U, Brodowski W, Diamantoglou M, et al. Dialysemembran mit verbesserter Biokompatibilität. German Patent, DE OS 3 1985; 524-96. 5. AKZO Faser AG. Hemophan, a modified membrane for dialysis US-Patent No. 4,668, 396; European Patent No. 172, 497 (1987). 6. Diamantoglou M, Lemke H, Vienken J. Cellulose ester as membrane material for hemodialysis. Int J Artif Organs 1994; 17: 385-91. 7. Diamantoglou M, Platz J, Vienken J. Cellulose-
8.
9.
10.
11. 12.
carbamates and derivatives as membrane materials for hemodialysis. Artif Organs 1999; 23: 15-23. Buck R, Göhl H. A permselective asymmetric membrane suitable for a hemodialysis and a process for manufacturing membranes. European Patent 1988; 305-587. Sluma H, Passlack J, Buttner B, Scherf M. Synthetic hydrophilic membranes and method of their manufacture. German Patent DE 4 112 508, 17.04 (1991). Streicher E, Schneider H. Polysulphone membrane mimicking human glomerular basement membrane. Lancet 1983; ii: 1136. Göhl H, Konstantin P, Gullberg C. Hemofiltration membranes. Contrib Nephrol 1982; 32: 20-30. Vienken J, Diamantoglou M, Kamusewitz H, Paul D. Considerations on developmental aspects of biocompatible membranes. Artif Organs 1995; 19: 398-406.
477
Polymers in nephrology
13. Clark W, Shinaberger J. Clinical evaulation of a new highefficiency hemodialyser: polysynthane. ASAIO J 2000; 46: 288-92. 14. Sasaki M, Hosoya N, Saruhashi M. Development of a vitamin E-bonded membrane. Contrib Nephrol 1999; 127: 49-70. 15. Center for Devices and Radiological Health, US Food & Drug Administration Safety assessment of di (2ethylhexyl) phthalate (DEHP) released from medical devices; From September 07, 2001 16. Klinkmann H, Davison A. The biocompatibility puzzle, partly solved, partly enigmatic. Nephrol Dial Transplant 1994; 9 (suppl 2): S184-6. 17. ANSI/AAMI/ISO 10993-4 (1993) Biological evaluation of medical devices, Part 4. Selection of tests for interactions with blood, p.3. 18. Basmadjian D, Sefton M. Coagulation on biomaterials in flowing blood: some theoretical considerations. Biomaterials 1997; 18: 1511-22. 19. Klinkmann H, Davison A, editors. Consensus Conference on Biocompatibility. Nephrol Dial Transplant 1994; 9 (suppl 2): S 1-186. 20. Cornelius R, Brash J. Identification of proteins adsorbed to hemodialyser membranes from heparinized blood. J Biomater Sci Polym Ed 1993; 4: 291-304. 21. Morti S, Zydney A. Protein-membrane interactions during hemodialysis: effects on solute transport. ASAIO J 1998; 44: 319-26. 22. Tielemanns C, Madoun P, Lenaers M, Schandene L, Goldman M, Vanherweghem J. Anaphylactoid reactions during hemodialysis on AN69 membranes in patients receiving ACE-inhibitors. Kidney Int 1990; 38: 982-4. 23. Parnes E, Shapiro W. Anaphylactoid reactions in hemodialysis patients treated with the AN69 dialyser. Kidney Int 1991; 40: 1148-52. 24. Brunet P, Jaber K, Berland Y, Baz M. Anaphylactoid reactions during hemodialysis and hemofiltration: role of associating AN69 membrane and angiotensin-converting enzyme. Am J Kidney Dis 1992; 19: 444-7. 25. Petrie J, Campbell Y, Hawley C, Hogan P. Anaphylactoid reactions in patients on hemodialysis with AN69 membranes whilst receiving ACE-inhibitors. Clin Nephrol 1991; 36: 264-5. 26. Schaefer R, Fink E, Schaefer L, Barkhausen R, Kulzer P, Heidland. A Role of bradykinin in anaphylactoid reactions during hemodialysis with AN69 dialysers. Am J Nephrol 1993; 13: 473-7. 27. Kammerl M, Schaefer R, Schweda F, Schreiber M, Riegger G, Kramer B. Extracorporeal therapy with AN69 membranes in combination with ACE-inhibition causing
478
28.
29.
30.
31.
32.
33.
34.
35.
36. 37. 38.
39.
40.
41.
42.
severe anaphylactoid reactions: still a current problem? Clin Nephrol 2000; 53: 486-8. Mannstadt M, Touam M, Fink E, et al. No generation of bradykinin with a new membrane (SPAN) in hemodialysis patients treated with ACE-inhibitors. Nephrol Dial Transplant 1995; 10: 1696-700. Kojima S, Harada-Shiba M, Nomura S, et al. Effect of nafamostat mesilate on bradykinin generation during LDL-apheresis using a dextran sulfate cellulose column. Trans ASAIO 1991; 37: 644-8. Van der Kamp K, von Oeveren W. Factor XII-fragment and kallikrein generation in plasma during incubation with bio-materials. J Biomed Mater Res 1994; 28: 349-52. Matata B, Wark S, Sundaram S, et al. In vitro contact phase activation with hemodialysis membranes: role of pharmaceutical agents. Biomaterials 1995; 16: 1305-12. Pegues D, Beck-Sague C, Wollen S, et al. Anaphylactoid reactions associated with reuse of hollow-fiber hemodialysers and ACE-inhibitors. Kidney Int 1992; 42: 1232-7. Coppo R, Amore A, Cirina P, et al. Bradykinin and nitric oxide generation by dialysis membranes can be blunted by alkaline rinsing solutions Kidney Int 2000; 58: 881-8. Werner C, Jacobasch H. Surface characterisation of polymers for medical devices. Int J Artif Organs 1999; 22: 160-76. Nakai S and the Patient Registration Committee of the Japanese Society for Dialysis Therapy. An overview of dialysis treatment in Japan. J Jpn Soc Dial Ther 2001; 34: 1121-47. Mettang T. The fate of leached DEHP in patients undergoing CAPD. Perit Dial Int 1996; 16: 58-62. Dolovich J, Bell B. Allergy to products of ethylene oxide gas. J Allergy Clin Immunol 1978; 62: 30-2. Grammer L, Patterson R. IgE against ethelyne oxidealtered human serum albumin as an etiologic agent in allergic reactions of hemodialysis patients. Artif Organs 1987; 11: 97-9. Handlos H. Hazards of ethylene oxide sterilisation Proc. Concept Symposium 3/81 on sterilisation procedures. Heildeberg 1981, pp. 90-2. Takesawa S, Satoh S, Hidai H, Sekiguchi M, Sakai K. Degradation by gamma irradiation of regenerated cellulose membranes for clinical dialysis. Trans ASAIO 1987; 33: 584-7. Bommer J, Miltenburger H, Hoerner V, Kilian S. Cytotoxicity of gray sterilized dialysis devices (abstract). J Am Soc Nephrol 1994; 5: 408. Shintani H, Nakamura A. Analysis of a carcinogen, 4,4’methylenedianiline, from thermosetting polyurethane
Vienken
during sterilisation. J Anal Toxicol 1989; 13: 354-7. 43. Mazzu A, Smith C. Determination of extractable methylene dianiline in thermoplastic polyurethanes by HPLC. J Biomed Mater Res 1984; 18: 961-8. 44. Hennig E, John A, Zartnack F, et al. Biostability of polyurethanes. Int J Artif Organs 1988; 11: 416-27. 45. Hutter J, Kuehnert M, Wallis R, Lucas A, Sen S, Jarvis W. Acute onset of decreased vision and hearing traced to hemodialysis treatment with aged dialysers. JAMA 2000; 283: 2128-34. 46. Oba T, Tsuji K, Nakamura A, et al. Migration of acetylated hemicellulose from capillary hemodialyser to blood,
causing scleritis and/or iritis. Artif Organs 1984; 8: 429-35. 47. Averbukh Z, Modai D, Sandbank J, et al. Red eye syndrome: clinical and experimental experience in a new aspect of diffuse eosinophilic infiltration. Artif Organs 2001; 25: 437-40. 48. Ferriman A. Baxter identifies processing fluid as possible cause of deaths. Br Med J 2001; 323: 1088. 49. Sass D, Russel A, van Dyke A, Wood E, Johnson S, Didisheim P. Gas embolism due to intravenous FC80 liquid fluorocarbon. J Appl Physiol 1976; 40: 745-51. 50. Henderson L. Dialysis in the 21st century. Am J Kidney Dis 1996; 28: 951-7.
479
