- Email: [email protected]
Influence of the dialysis membrane on outcome of ESRD patients
Influence of the Dialysis Membrane on Outcome of ESRD Patients Raymond M. Hakim, MD, PhD ● Data from the US Renal Data System (USRDS) document a substantial reduction in the use of cellulosic membranes, from approximately 70% in 1990 to less than 20% in 1996. These changes have been accompanied by a reduction in the adjusted mortality of patients with end-stage renal disease (ESRD) in the United States. The possibility that this association between the changes in the nature of the membrane and clinical outcome represents a cause-and-effect relationship is discussed in terms of the known biochemical actions of complement activation, consequent neutrophil and monocyte activation, and clinical studies that have been published comparing membranes with different biocompatibilities. Together, these studies support a role for the changes in the biocompatibility of dialysis membranes in the improvement of ESRD patient mortality in the United States. r 1998 by the National Kidney Foundation, Inc. INDEX WORDS: Biocompatibility; complement; outcome.
T
HE PERIOD of time since the 1989 conference on the Morbidity, Mortality and Prescription of Dialysis held in Dallas, TX, until the present state-of-the-art Strategies for Influencing Outcomes in Pre-ESRD and ESRD Patients conference has been a time of substantial changes in a few areas of end-stage renal disease (ESRD) practice, whereas other areas have remained relatively unchanged. As aptly described by the organizers of the conference, there have been ‘‘improvements in the prescription management, better scientific understanding of some of the key processes in dialysis management . . . ,’’ coupled with outstanding comprehensive data sources, primarily from the United States Renal Data System (USRDS). Whereas the mortality of dialysis-dependent patients still remains unacceptably high, analysis presented at the Strategies for Influencing Outcomes in Pre-ESRD and ESRD Patients conference (see article by Wolfe et al1) suggests that after adjusting for major comorbid factors, namely demographic variables (age, sex, race) and diabetic status, the standardized mortality rate is declining in the United States. This is certainly welcome news, and it is tempting to attribute these improvements in mortality to changes in the prescription and, more importantly, the delivery of dialysis since 1989. Increases in the dose of delivered dialysis have clearly occurred; expressed as Kt/V, the average delivered dose of dialysis was 1.1 for prevalent patients in 1990 and 1.18 in 1996 to 1997. Nevertheless, these changes in delivered dialysis dose have, on average, been modest and explain only part of the improvements in the adjusted mortality. During this conference, Fritz
Port from the USRDS estimated that only approximately 50% of the decrease in mortality can be attributed to the improvement in the dose of dialysis when one calculates the known relationship between the dose of dialysis and mortality.2 Another important change that has occurred is a fairly substantive change in the type of dialysis membranes used in the delivery of dialysis. This is shown in Fig 1, from data derived by the USRDS. In 1990, 70% of all dialysis membranes were a cellulosic type dialyzer, with only 9% of the membranes labeled synthetic; in 1996, the fraction of cellulosic membranes used was less than 20%, with 57% of the membranes considered synthetic, and early indications are that this proportion of synthetic membrane usage is increasing further in 1997. The proportion of membranes, so-called modified cellulosic or semisynthetic (such as the cellulose triacetate), have remained at approximately 20%. It is worthwhile to ask, therefore, why has this change occurred and what is its potential impact on the mortality of dialysis patients in the United States. BIOLOGICAL AND CLINICAL EFFECTS OF THE DIALYSIS MEMBRANE
Biochemical Reactions at the Blood-Membrane Interface Complement system. During the contact of blood with dialysis membrane, several protein-
From the Renal Care Group, Nashville, TN. Address reprint requests to Raymond M. Hakim, MD, PhD, Renal Care Group, 2100 West End Ave, Suite 800, Nashville, TN 37203. E-mail: [email protected]
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3206-0412$3.00/0
American Journal of Kidney Diseases, Vol 32, No 6, Suppl 4 (December), 1998: pp S71-S75
S71
S72
Fig 1. Dialyzer membrane type used for incident hemodialysis patients by year, 1990 to 1997. USRDS Special Study Data. Abbreviations: CMAS, Case Mix Adequacy Study; DMMSW-1, Dialysis Morbidity and Mortality Study; 䊏, unclassified; 䊐, synthetic; M, modified cellulose; O, cellulose.
mediated and cellular pathways are activated. Historically, the pathway first discussed was the activation of the complement pathway. Because of its widespread systemic effects in several animal models and its direct and indirect actions, (ie, activation of cellular pathways through their complement receptors), it is an important index of the biocompatibility of dialysis membranes. The polysaccharide nature of cellulosic membrane makes it a particularly suitable trigger for the initiation of the alternative pathway of complement.3-5 Once initiated, this pathway results in the formation of anaphylatoxins C3a and C5a and the membrane attack complex (MAC, or C5b-9) that is formed by the combination of C5b, C6, C7, C8, and C9. Activated components of complement are acted on by plasma factors that inactivate them. Specifically, C3a and C5a are transformed into C3a-desarginine and C5adesarginine, and the MAC is quickly taken up by red blood cell membranes. Nevertheless, nascent C5a and, to a lesser extent, C5a-desarginine extent are able to induce the activation of phagocytes, including neutrophils and monocytes, through their complement receptors.5-7 Several indices of granulocyte activation have also been shown during hemodialysis with cellulosic membranes. These include increased expression of adhesion surface receptors,8,9 degranulation and release of enzymes,10 and enhanced oxidative metabolism resulting in the formation of reactive oxygen species (ROS).6 Monocytes
RAYMOND M. HAKIM
are also activated by complement products; they are the principal circulating cells involved in elaboration of monokines, such as interleukin-1 and tumor necrosis factor. The biocompatibility of the membrane, usually defined in terms of its ability to activate complement, may also be defined in terms of the activation of the monocytes or their elaboration of cytokines.11,12 More recent data suggest that platelets also participate in blood-membrane interactions, and such interactions are manifested not only by a rapid platelet turnover in hemodialysis patients, but also lead to membrane-specific release of the products of thromboxanes (LTB4 and LTC4). Finally, an increase in platelet-leukocyte coaggregates has been shown during dialysis with cellulosic membranes (but not with PAN membrane) by flow cytometry techniques. Indeed, the report suggests that hydrogen peroxide and other ROS formation by neutrophils is primarily by neutrophil-platelet aggregates and not by neutrophils unaggregated to platelets.13 A possible link between these observations is the increased production of platelet-activating factors during dialysis with complement-activating membranes.14 There is increasing evidence that unregulated free radical formation may be involved in various disease processes, such as the pathogenesis of pulmonary endothelial injury during oxygen exposure and adult respiratory distress syndrome.15-17 There is also evidence that ROS are involved in tissue injury as a result of ischemia followed by reperfusion in the myocardium and other tissue beds,18 and a hypothesis for their involvement in the increased prevalence of cardiovascular disease has been postulated recently.19 In other models, lipid peroxidation by oxygen radicals has been shown to enhance the potential for atherogenesis, a hallmark of longterm dialysis patients.19 Recent studies have also shown a dialysis membrane–dependent increase in nitric oxide during dialysis, which was significantly greater in patients dialyzing with cellulosic membranes compared with biocompatible membranes.20 Contact activation pathway. In addition to complement activation, other protein pathways have the potential to be activated with different membranes. The contact pathway is activated by some membranes that have a high negative surface charge, such as the polyacrylonitrite mem-
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S73
brane, and this may have a role in the reported incidence of anaphylactic reactions associated with some of the newer synthetic membranes, particularly in patients taking angiotensin-converting enzyme inhibitors, which also inhibit the kininase enzyme and, thus, the degradation of bradykinin.21,22 Indeed, this points to the complexity of defining a biocompatible membrane, because some of the membranes that are associated with low (net) complement activation are also membranes that may vigorously activate the contact pathway.23
a 30% relative risk for infection of patients dialyzed with the polysulfone biocompatible membrane compared with patients dialyzed with the cellulosic membrane. Finally, a study by Koda et al29 that compared the outcome of 819 patients (4,543 patient years) dialyzed in a single center over a 25-year period found that patients dialyzed with high-flux biocompatible membranes had a relative risk of 0.64 for the development of carpal tunnel syndrome and 0.613 for mortality compared with patients dialyzed with cellulosic membranes.30 However, such a difference in mortality or morbidity was not seen in an Italian study of 380 patients enrolled into four treatment modalities in 71 centers, with a follow-up of 2 years.31
Effect of the Membrane on Clinical Outcome A role for the biocompatibility of the dialysis membrane in the survival of patients undergoing chronic hemodialysis was shown in a recent historical prospective study design, based on a random sample of approximately 6,000 patients analyzed by the USRDS. By comparing the mortality of subgroups of patients chronically dialyzed with cellulosic, semisynthetic, and synthetic membranes, and after adjusting for the dose of dialysis as well as other comorbidities, patients dialyzing with low complement-activating membranes, such as the synthetic and semisynthetic membranes, had a relative risk for mortality that was at least 25% lower in that group compared with patients chronically dialyzed with cellulosic membranes.24 Potential contributing factors to the increased survival of chronic hemodialysis patients dialyzed with biocompatible membranes are the improved preservation of residual renal function25 and the improved nutritional status of such patients compared with patients dialyzed with cellulosic membranes.26 Two other studies have confirmed the observations that the use of biocompatible (non–complement-activating) membranes is associated with a significant reduction in the incidence of infection in hemodialysis patients.27,28 Hornberger et al27 reported reduction of the rate of hospitalization for infectious causes from 0.024 d/mon/patient to 0.011 d/mon/patient in patients dialyzed with a polysulfone membrane. A similar decline has also been reported in another study, reported in abstract form, of approximately 1,000 patients who were studied before and after their dialysis membranes were switched from cellulosic to biocompatible membranes. Levin et al28 reported
Potential Role of Flux on Outcome A confounding issue about the association between clinical outcomes and biocompatibility is that most of the studies that have shown a membrane-based difference in outcome used membranes that differ from the cellulosic reference membrane, not only in their ability to activate the complement system systematically, but also in their flux characteristics; thus, the possibility exists that these differences in outcome are caused by differences in flux characteristics, rather than differences in their overall biocompatibility characteristics. Whereas flux characteristics may account for some of the differences in outcome, there are no biochemical studies that have identified a specific middle molecule that may be diseasecausing, except for B2m. In this regard, it is worth noting that although comparisons between patients dialyzed with high-flux membranes and cellulosic membranes show differences in microglobulin (B2m) concentrations that may explain differences in the incidence of amyloid bone disease, these differences in B2m concentrations are for the most part modest and do not correlate with the incidence of the disease. Indeed, based on this and other similar observations, the possibility that the formation of ROS during the use of cellulosic membranes may have a direct role in the elaboration of B2m and the subsequent polymerization of B2m and/or transformation into AGE-derived moities has been proposed.32 Conversely, it is clear that the myriad actions of complement activation on neutrophils and
S74
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monocyte activation lend plausibility to a direct link between complement activation and clinical outcome. Thus, the studies by Parker et al26 that showed membrane-based differences in nutritional outcome were performed comparing membranes with similar (low) flux but with differences in complement activation. CONCLUSION
There are at present no randomized studies to judge the effects of dialysis membrane biocompatibility on the serious morbidity (ie, hospitalization) and mortality of chronic hemodialysis patients. Thus, although the absolute proof (ie, beyond a reasonable doubt) of a cause-and-effect relationship between the changes in the type of dialysis membranes from 1990 to 1997 and the changes in adjusted mortality is still lacking, almost all studies support the possibility that the use of biocompatible membranes is associated with improvement in morbidity and mortality when compared with patients dialyzed with the cellulosic membrane. These studies should also be viewed in the context that there are no studies that have documented a beneficial effect of cellulosic membranes on the morbidity and mortality of patients with ESRD. REFERENCES 1. Wolfe RA, Held PJ, Hulbert-Shearon TE, Agodoa LYC, Port FK: A critical examination of trends in outcomes over the past decade. Am J Kidney Dis 32:S9-S15, 1998 (suppl 4) 2. Held PJ, Port FK, Wolfe RA, Stannard DC, Carroll CE, Jaugirdas JT, Bloembergen WE, Greer JW, Hakim RM: The dose of hemodialysis and patient mortality. Kidney Int 50:550-556, 1996 3. Kaplow LS, Goffinet JA: Profound neutropenia during the early phase of hemodialysis. JAMA 203:1135-1137, 1968 4. Craddock PR, Fehr J, Delmasso AP, Brigham KL, Jacob HS: Hemodialysis leukopenia: Pulmonary vascular leukostasis resulting from complement activation by dialyzer cellophane membranes. J Clin Invest 59:878-888, 1977 5. Hakim RM, Fearon DT, Lazarus JM: Biocompatibility of dialysis membranes: Effects of chronic complement activation. Kidney Int 26:194-210, 1984 6. Himmelfarb J, Lazarus M, Hakim R: Reactive oxygen species production by monocytes and polymorphonuclear leukocytes during dialysis. Am J Kidney Dis 3:271-276, 1991 7. Himmelfarb J, Zaoui P, Holbrook D, Hakim RM: Modulation of granulocyte LAM-1 and MAC-1 during dialy-
sis—A prospective, randomized controlled trial. Kidney Int 41:388-395, 1992 8. Arnout MA, Hakim RM, Todd RF, Dana N, Colten HR: Increased expression of an adhesion promoting surface glycoprotein in the granulocytopenia of hemodialysis. N Engl J Med 312:457-462, 1985 9. Castiglione A, Pagliaro P, Romagnoni M, Beccari M, Cavaliere G, Veneroni G: Flow cytometric analysis of leukocytes eluted from haemodialysis. Nephrol Dial Transplant 2:31-35, 1991 10. Horl WH, Schaefer RM, Heidland A: Effect of different dialyzers on proteinase and proteinase inhibitors during hemodialysis. Am J Nephrol 5:320-326, 1985 11. Lin YF, Chang DM, Lu KC, Chyr SH, Li BL, Sheih SD: Cytokine production during hemodialysis: Effects of dialytic membrane and complement activation. Am J Nephrol 16:293-299, 1996 12. Betz M, Haensch GM, Rauterberg EW, Bommer J, Ritz E: Cuprammonium membranes stimulate interleukin-1 release and arachidonic acid metabolism in monocytes in the absence of complement. Kidney Int 34:67-73, 1988 13. Bonomini M, Stuard S, Carreno MP, Settefrati N, Santarelli P, Haeffner-Cavaillon N, Albertazzi A: Neutrophil reactive oxygen species production during hemodialysis: Role of activated platelet adhesion to neutrophils through p-selectin. Nephrol 75:402-411, 1997 14. Guastoni C, Tetta C, Hoenich NA, Gervasio R, Sereni L, Tessore E, Wratten ML, Civati G: Mechanisms and kinetics of the synthesis and release of platelet-activating factor (PAF) by polyacrylonitrite membranes. Clin Nephrol 46:132-138, 1996 15. Kunkel SL, Strieter RM: Cytokine networking in lung inflammation. Hosp Prac 25:63-76, 1990 16. Perkowski SZ, Havill AM, Flynn JT, Gee MH: Role of intrapulmonary release of eicosanoids and superoxide anion as mediators of pulmonary dysfunction and endothelial injury in sheep with intermittent complement activation. Circ Res 53:574-583, 1983 17. Ward PA, Till GO, Hatherill JR, Annesley TM, Knunkel RG: Systemic complement activation, lung injury, and products of lipid peroxidation. J Clin Invest 76:517-527, 1985 18. Halliwell B, Gutteridge JMC, Cross CE: Free radicals, antioxidants and human disease: Where are we now? J Lab Clin Med 119:598-620, 1992 19. Becker BN, Himmelfarb J, Henrich WL, Hakim RM: Reassessing the cardiac risk profile in chronic hemodialysis patients: A hypothesis on the role of oxidant strett and other non-traditional cardiac risk factors. J Am Soc Nephrol 8:475486, 1997 20. Rysz J, Luciak M, Kedziora J, Blaszczyk J, Sibinska E: Nitric oxide release in the peripheral blood during hemodialysis. Kidney Int 51:294-300, 1997 21. Schulman G, Hakim RM, Arias R, Silverberg M, Kaplan AP, Arbeit L: Bradykinin generation by dialysis membranes: Possible role in anaphylactic reaction. J Am Soc Nephrol 3:1563-1569, 1993 22. Thomaneck Y, Vienken J, Waldschlager U, et al: Detection of charges and their distribution on dialysis membranes with cationic/anionic dyes using confocal laser scanning microscopy. Int J Artif Organs 14:686-690, 1991
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23. Cheung AK, Chenoweth DE, Otsuka D, Henderson LW: Compartmental distribution of complement activation products in artificial kidneys. Kidney Int 30:74-80, 1986 24. Hakim RM, Held PJ, Stannard DC, Wolfe RA, Port FK, Daugirdas JT, Agodoa L: Effect of the dialysis membrane on mortality of chronic hemodialysis patients. Kidney Int 50:566-570, 1996 25. McCarthy JT, Jenson BM, Squillace DP, Williams AW: Improved preservation of residual renal function in chronic hemodialysis patients using polysulfone dialyzers. Am J Kidney Dis 29:576-583, 1997 26. Parker TF, Wingard RL, Husni L, Ikizler TA, Parker RA, Hakim RM: Effect of the membrane biocompatibility on nutritional parameters in chronic hemodialysis patients. Kidney Int 49:551-556, 1996 27. Hornberger JC, Chernew M, Petersen J, Garber AM: A multivariate analysis of mortality and hospital admissions with high-flux dialysis. J Am Soc Nephrol 3:1227-1237, 1993 28. Levin NW, Zasuwa G, Dumler F: Effect of membrane
types on causes of death in hemodialysis patients. J Am Soc Nephrol 2:335, 1991 (abstr) 29. Koda Y, Nishi S, Miyazaki S, Haginoshita S, Sakurabayashi T, Suzuki M, Sakai S, Yuasa Y, Hirasawa Y, Nishi T: Switch from conventional to high-flux membrane reduces the risk of carpal tunnel syndrome and mortality of hemodialysis patients. Kidney Int 52:1096-1101, 1997 30. Hakim RM: The influence of high-flux biocompatible membrane on carpal tunnel syndrome and mortality. Am J Kidney Dis 32:338-343, 1998 31. Locatelli F, Mastrangelo F, Redaelli B, Ronco C, Marcelli D, La Greca G, Orlandini G, and the Italian Cooperative Dialysis Study Group: Effects of different membranes and dialysis technologies on patient treatment tolerance and nutritional parameters. Kidney Int 50:1293-1302, 1996 32. Zaoui P, Harrington R, Lee W, Hoover R, Lawrence P, Hakim R: Interaction of activated neutrophils with endothelial cells leads to increased generation of B2m microglobulin. J Am Soc Nephrol 2:356, 1991 (abstr)
T
HE PERIOD of time since the 1989 conference on the Morbidity, Mortality and Prescription of Dialysis held in Dallas, TX, until the present state-of-the-art Strategies for Influencing Outcomes in Pre-ESRD and ESRD Patients conference has been a time of substantial changes in a few areas of end-stage renal disease (ESRD) practice, whereas other areas have remained relatively unchanged. As aptly described by the organizers of the conference, there have been ‘‘improvements in the prescription management, better scientific understanding of some of the key processes in dialysis management . . . ,’’ coupled with outstanding comprehensive data sources, primarily from the United States Renal Data System (USRDS). Whereas the mortality of dialysis-dependent patients still remains unacceptably high, analysis presented at the Strategies for Influencing Outcomes in Pre-ESRD and ESRD Patients conference (see article by Wolfe et al1) suggests that after adjusting for major comorbid factors, namely demographic variables (age, sex, race) and diabetic status, the standardized mortality rate is declining in the United States. This is certainly welcome news, and it is tempting to attribute these improvements in mortality to changes in the prescription and, more importantly, the delivery of dialysis since 1989. Increases in the dose of delivered dialysis have clearly occurred; expressed as Kt/V, the average delivered dose of dialysis was 1.1 for prevalent patients in 1990 and 1.18 in 1996 to 1997. Nevertheless, these changes in delivered dialysis dose have, on average, been modest and explain only part of the improvements in the adjusted mortality. During this conference, Fritz
Port from the USRDS estimated that only approximately 50% of the decrease in mortality can be attributed to the improvement in the dose of dialysis when one calculates the known relationship between the dose of dialysis and mortality.2 Another important change that has occurred is a fairly substantive change in the type of dialysis membranes used in the delivery of dialysis. This is shown in Fig 1, from data derived by the USRDS. In 1990, 70% of all dialysis membranes were a cellulosic type dialyzer, with only 9% of the membranes labeled synthetic; in 1996, the fraction of cellulosic membranes used was less than 20%, with 57% of the membranes considered synthetic, and early indications are that this proportion of synthetic membrane usage is increasing further in 1997. The proportion of membranes, so-called modified cellulosic or semisynthetic (such as the cellulose triacetate), have remained at approximately 20%. It is worthwhile to ask, therefore, why has this change occurred and what is its potential impact on the mortality of dialysis patients in the United States. BIOLOGICAL AND CLINICAL EFFECTS OF THE DIALYSIS MEMBRANE
Biochemical Reactions at the Blood-Membrane Interface Complement system. During the contact of blood with dialysis membrane, several protein-
From the Renal Care Group, Nashville, TN. Address reprint requests to Raymond M. Hakim, MD, PhD, Renal Care Group, 2100 West End Ave, Suite 800, Nashville, TN 37203. E-mail: [email protected]
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3206-0412$3.00/0
American Journal of Kidney Diseases, Vol 32, No 6, Suppl 4 (December), 1998: pp S71-S75
S71
S72
Fig 1. Dialyzer membrane type used for incident hemodialysis patients by year, 1990 to 1997. USRDS Special Study Data. Abbreviations: CMAS, Case Mix Adequacy Study; DMMSW-1, Dialysis Morbidity and Mortality Study; 䊏, unclassified; 䊐, synthetic; M, modified cellulose; O, cellulose.
mediated and cellular pathways are activated. Historically, the pathway first discussed was the activation of the complement pathway. Because of its widespread systemic effects in several animal models and its direct and indirect actions, (ie, activation of cellular pathways through their complement receptors), it is an important index of the biocompatibility of dialysis membranes. The polysaccharide nature of cellulosic membrane makes it a particularly suitable trigger for the initiation of the alternative pathway of complement.3-5 Once initiated, this pathway results in the formation of anaphylatoxins C3a and C5a and the membrane attack complex (MAC, or C5b-9) that is formed by the combination of C5b, C6, C7, C8, and C9. Activated components of complement are acted on by plasma factors that inactivate them. Specifically, C3a and C5a are transformed into C3a-desarginine and C5adesarginine, and the MAC is quickly taken up by red blood cell membranes. Nevertheless, nascent C5a and, to a lesser extent, C5a-desarginine extent are able to induce the activation of phagocytes, including neutrophils and monocytes, through their complement receptors.5-7 Several indices of granulocyte activation have also been shown during hemodialysis with cellulosic membranes. These include increased expression of adhesion surface receptors,8,9 degranulation and release of enzymes,10 and enhanced oxidative metabolism resulting in the formation of reactive oxygen species (ROS).6 Monocytes
RAYMOND M. HAKIM
are also activated by complement products; they are the principal circulating cells involved in elaboration of monokines, such as interleukin-1 and tumor necrosis factor. The biocompatibility of the membrane, usually defined in terms of its ability to activate complement, may also be defined in terms of the activation of the monocytes or their elaboration of cytokines.11,12 More recent data suggest that platelets also participate in blood-membrane interactions, and such interactions are manifested not only by a rapid platelet turnover in hemodialysis patients, but also lead to membrane-specific release of the products of thromboxanes (LTB4 and LTC4). Finally, an increase in platelet-leukocyte coaggregates has been shown during dialysis with cellulosic membranes (but not with PAN membrane) by flow cytometry techniques. Indeed, the report suggests that hydrogen peroxide and other ROS formation by neutrophils is primarily by neutrophil-platelet aggregates and not by neutrophils unaggregated to platelets.13 A possible link between these observations is the increased production of platelet-activating factors during dialysis with complement-activating membranes.14 There is increasing evidence that unregulated free radical formation may be involved in various disease processes, such as the pathogenesis of pulmonary endothelial injury during oxygen exposure and adult respiratory distress syndrome.15-17 There is also evidence that ROS are involved in tissue injury as a result of ischemia followed by reperfusion in the myocardium and other tissue beds,18 and a hypothesis for their involvement in the increased prevalence of cardiovascular disease has been postulated recently.19 In other models, lipid peroxidation by oxygen radicals has been shown to enhance the potential for atherogenesis, a hallmark of longterm dialysis patients.19 Recent studies have also shown a dialysis membrane–dependent increase in nitric oxide during dialysis, which was significantly greater in patients dialyzing with cellulosic membranes compared with biocompatible membranes.20 Contact activation pathway. In addition to complement activation, other protein pathways have the potential to be activated with different membranes. The contact pathway is activated by some membranes that have a high negative surface charge, such as the polyacrylonitrite mem-
INFLUENCE OF DIALYSIS MEMBRANE ON OUTCOME
S73
brane, and this may have a role in the reported incidence of anaphylactic reactions associated with some of the newer synthetic membranes, particularly in patients taking angiotensin-converting enzyme inhibitors, which also inhibit the kininase enzyme and, thus, the degradation of bradykinin.21,22 Indeed, this points to the complexity of defining a biocompatible membrane, because some of the membranes that are associated with low (net) complement activation are also membranes that may vigorously activate the contact pathway.23
a 30% relative risk for infection of patients dialyzed with the polysulfone biocompatible membrane compared with patients dialyzed with the cellulosic membrane. Finally, a study by Koda et al29 that compared the outcome of 819 patients (4,543 patient years) dialyzed in a single center over a 25-year period found that patients dialyzed with high-flux biocompatible membranes had a relative risk of 0.64 for the development of carpal tunnel syndrome and 0.613 for mortality compared with patients dialyzed with cellulosic membranes.30 However, such a difference in mortality or morbidity was not seen in an Italian study of 380 patients enrolled into four treatment modalities in 71 centers, with a follow-up of 2 years.31
Effect of the Membrane on Clinical Outcome A role for the biocompatibility of the dialysis membrane in the survival of patients undergoing chronic hemodialysis was shown in a recent historical prospective study design, based on a random sample of approximately 6,000 patients analyzed by the USRDS. By comparing the mortality of subgroups of patients chronically dialyzed with cellulosic, semisynthetic, and synthetic membranes, and after adjusting for the dose of dialysis as well as other comorbidities, patients dialyzing with low complement-activating membranes, such as the synthetic and semisynthetic membranes, had a relative risk for mortality that was at least 25% lower in that group compared with patients chronically dialyzed with cellulosic membranes.24 Potential contributing factors to the increased survival of chronic hemodialysis patients dialyzed with biocompatible membranes are the improved preservation of residual renal function25 and the improved nutritional status of such patients compared with patients dialyzed with cellulosic membranes.26 Two other studies have confirmed the observations that the use of biocompatible (non–complement-activating) membranes is associated with a significant reduction in the incidence of infection in hemodialysis patients.27,28 Hornberger et al27 reported reduction of the rate of hospitalization for infectious causes from 0.024 d/mon/patient to 0.011 d/mon/patient in patients dialyzed with a polysulfone membrane. A similar decline has also been reported in another study, reported in abstract form, of approximately 1,000 patients who were studied before and after their dialysis membranes were switched from cellulosic to biocompatible membranes. Levin et al28 reported
Potential Role of Flux on Outcome A confounding issue about the association between clinical outcomes and biocompatibility is that most of the studies that have shown a membrane-based difference in outcome used membranes that differ from the cellulosic reference membrane, not only in their ability to activate the complement system systematically, but also in their flux characteristics; thus, the possibility exists that these differences in outcome are caused by differences in flux characteristics, rather than differences in their overall biocompatibility characteristics. Whereas flux characteristics may account for some of the differences in outcome, there are no biochemical studies that have identified a specific middle molecule that may be diseasecausing, except for B2m. In this regard, it is worth noting that although comparisons between patients dialyzed with high-flux membranes and cellulosic membranes show differences in microglobulin (B2m) concentrations that may explain differences in the incidence of amyloid bone disease, these differences in B2m concentrations are for the most part modest and do not correlate with the incidence of the disease. Indeed, based on this and other similar observations, the possibility that the formation of ROS during the use of cellulosic membranes may have a direct role in the elaboration of B2m and the subsequent polymerization of B2m and/or transformation into AGE-derived moities has been proposed.32 Conversely, it is clear that the myriad actions of complement activation on neutrophils and
S74
RAYMOND M. HAKIM
monocyte activation lend plausibility to a direct link between complement activation and clinical outcome. Thus, the studies by Parker et al26 that showed membrane-based differences in nutritional outcome were performed comparing membranes with similar (low) flux but with differences in complement activation. CONCLUSION
There are at present no randomized studies to judge the effects of dialysis membrane biocompatibility on the serious morbidity (ie, hospitalization) and mortality of chronic hemodialysis patients. Thus, although the absolute proof (ie, beyond a reasonable doubt) of a cause-and-effect relationship between the changes in the type of dialysis membranes from 1990 to 1997 and the changes in adjusted mortality is still lacking, almost all studies support the possibility that the use of biocompatible membranes is associated with improvement in morbidity and mortality when compared with patients dialyzed with the cellulosic membrane. These studies should also be viewed in the context that there are no studies that have documented a beneficial effect of cellulosic membranes on the morbidity and mortality of patients with ESRD. REFERENCES 1. Wolfe RA, Held PJ, Hulbert-Shearon TE, Agodoa LYC, Port FK: A critical examination of trends in outcomes over the past decade. Am J Kidney Dis 32:S9-S15, 1998 (suppl 4) 2. Held PJ, Port FK, Wolfe RA, Stannard DC, Carroll CE, Jaugirdas JT, Bloembergen WE, Greer JW, Hakim RM: The dose of hemodialysis and patient mortality. Kidney Int 50:550-556, 1996 3. Kaplow LS, Goffinet JA: Profound neutropenia during the early phase of hemodialysis. JAMA 203:1135-1137, 1968 4. Craddock PR, Fehr J, Delmasso AP, Brigham KL, Jacob HS: Hemodialysis leukopenia: Pulmonary vascular leukostasis resulting from complement activation by dialyzer cellophane membranes. J Clin Invest 59:878-888, 1977 5. Hakim RM, Fearon DT, Lazarus JM: Biocompatibility of dialysis membranes: Effects of chronic complement activation. Kidney Int 26:194-210, 1984 6. Himmelfarb J, Lazarus M, Hakim R: Reactive oxygen species production by monocytes and polymorphonuclear leukocytes during dialysis. Am J Kidney Dis 3:271-276, 1991 7. Himmelfarb J, Zaoui P, Holbrook D, Hakim RM: Modulation of granulocyte LAM-1 and MAC-1 during dialy-
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