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J Am Soc Nephrol 13:S62-S71, 2002
© 2002 American Society of Nephrology

Hemodialysis

Hemodialysis Membranes: Interleukins, Biocompatibility, and Middle Molecules

Walter H. Hörl

Department of Medicine, Division of Nephrology, University of Vienna, Vienna, Austria.

Correspondence to Dr. Walter H. Hörl, Department of Medicine III, University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Phone: +43-1-40400-4390; Fax: +43-1-40400-4392; E-mail: walter.hoerl{at}nephro.imed3.akh-wien.ac.at

Abstract

ABSTRACT. Maintenance hemodialysis patients display evidence of elevated interleukin-1 (IL-1) and tumor necrosis factor alpha release after stimulation either by contaminated dialysate, bioincompatible membrane material, or both. This release is followed by the stimulated secretion of a large number of other interleukins, particularly IL-6, the cytokine principally responsible for acute-phase protein synthesis. It has been shown that high levels of the circulating proinflammatory cytokines IL-1, tumor necrosis factor alpha, IL-6, and IL-13 are associated with mortality in hemodialysis patients. Essential functions of polymorphonuclear leukocytes—that is, phagocytosis, oxygen species production, upregulation of specific cell surface receptor proteins, or apoptosis—are disturbed in patients with end-stage renal disease. These are further altered as a result of complement activation by the hemodialysis procedure, particularly if bioincompatible dialyzers are used. Polymorphonuclear leukocyte degranulation occurring during extracorporeal circulation does not depend on complement activation but rather on intracellular calcium and the presence or absence of the degranulation inhibitory proteins angiogenin and complement factor D. Clinical signs and symptoms of end-stage renal disease patients are at least in part related to the accumulation of middle molecules such as ß2-microglobulin, parathyroid hormone, advanced glycation end products, advanced lipoxidation end products, advanced oxidation protein products (formed as a result of oxidative stress, carbonyl stress, or both), granulocyte inhibitory proteins, or leptin. Currently available membrane materials do not provide long-lasting, effective reduction of middle molecules in patients who require maintenance hemodialysis.

Hemodialysis therapy may induce activation of complement and blood cells such as polymorphonuclear leukocytes (PMNL), monocytes, or lymphocytes, depending on the membrane material of the dialyzer used. The clinical situation of the patient with end-stage renal disease (ESRD) is further complicated by the accumulation of uremic retention solutes and uremic toxins, which are often inadequately removed during the three-times-per-week dialysis procedure. The following overview focuses on interleukins, biocompatibility, and middle molecules and their relationships to different dialyzer membranes.

Mononuclear Cells
Effect of Uremia and Hemodialysis
Patients undergoing hemodialysis via routine regenerated cellulose membranes show evidence of elevated interleukin-1 (IL-1) and tumor necrosis factor (TNF) before a dialysis session and a further increase at the end of the procedure (1–5). Not all studies, however, confirm these findings. Cytokine production is not only related to hemodialysis with cellulosic membranes; it has also been shown that patients undergoing regular hemodialysis treatment with hemophane or polyamide dialyzers have comparable plasma concentrations of IL-1ß, IL-6, and IL-10 predialysis at the end of the first treatment and after 48 treatments (4 mo) (6). Analysis of peripheral blood mononuclear cells (PBMC) is more likely to yield consistent results regarding increased cytokine production during hemodialysis treatment than circulating plasma concentrations (7). IL-1 is present in the mononuclear cells of patients undergoing regular hemodialysis (5,8–10), but not in mononuclear cells isolated from healthy subjects. PBMC from hemodialysis patients are "primed" to produce increased levels of IL-1ß and TNF upon in vitro stimulation (4,5,11). In contrast to studies with isolated monocytes, Le Meur et al. (12) found that monocytes from hemodialysis patients in whole blood cultures are hyporesponsive to phytohemagglutinin or lipopolysaccharide (LPS). This finding might partly explain the immune defect in uremic and hemodialysis patients, if it reflects the in vivo situation (12). It is possible that the cell separation procedure affects the response of PBMC.

Mononuclear cells exiting the cuprophane dialyzer have initiated transcription to express large amounts of IL-1ß and TNF-{alpha}, whereas cytokine genes are not activated by non-complement-activating membranes during dialysis (13,14). The anaphylaxins C5a and C3a may stimulate cytokine synthesis (15), particularly in the presence of endotoxin (16). Concentrations of the monokine IL-1ß in PBMC supernatants cultured for 24 h with 500 ng/ml LPS were significantly lower after dialysis in patients treated with polyamide when compared with those treated with hemophane (6). In the study of Memoli et al. (17), PBMC were cultured for 48 h with and without nonspecific mitogen stimulation. In unstimulated conditions, PBMC harvested from patients who underwent dialysis with the cuprophane membrane showed higher IL-12 production than PBMC of healthy subjects, uremic patients who did not undergo dialysis, and patients who underwent dialysis with the biocompatible polymethylmethacrylate (PMMA) membrane. IL-12 production was correlated with C3a concentration. Under stimulation, PBMC interferon gamma release was lower in patients who underwent dialysis with cuprophane membranes as compared with PBMC obtained from patients who underwent dialysis with PMMA membranes, from uremic patients who did not undergo dialysis, or from healthy subjects. It was concluded that the altered release of interferon gamma could play a role in cell-mediated immunodeficiency of the uremic patients who underwent dialysis with cuprophane membranes (17). Girndt et al. (18) measured cytokine induction in lymphocytes obtained from patients undergoing regular hemodialysis treatment with hemophane dialyzers. These patients were entered into a crossover study with a vitamin E-coated cuprophane (VE) dialyzer or a synthetic polyamide dialyzer. Four weeks of treatment with either VE or polyamide dialyzer enhanced in vitro proliferation of peripheral blood leukocytes as compared with treatment with the hemophane membranes used before study entry. The VE membrane reduced acute production of IL-6 during dialysis, whereas the regulatory cytokine IL-10 was not affected. It was concluded that the VE membrane, despite being based on a cuprophane backbone, is similar to the highly biocompatible polyamide dialyzer in terms of its effect on lymphocyte function (18).

LPS and LPS fragments containing the lipid A subunit bind to the LPS-binding protein (LBP). The LBP-LPS complex binds to the CD14 receptor on mononuclear cells resulting in de novo synthesis of cytokines. Neutrophils produce the bactericidal permeability inhibitory protein (BPI), which competes with LBP for the same binding domain on LPS. BPI inhibits LPS-dependent cytokine induction in mononuclear cells because the BPI-LPS complex does not bind to the CD14 receptor. The balance between BPI and LBP may determine LPS activity (19). Plasma BPI levels, however, are one order of magnitude lower than LBP levels, indicating no inhibitory effect of BPI on LPS in dialysis patients (20). The secretion of IL-1 and TNF-{alpha} is followed by the stimulated secretion of a large number of other interleukins, particularly IL-6, the cytokine principally responsible for acute-phase protein synthesis (e.g., stimulation of C-reactive protein and serum amyloid A, inhibition of albumin synthesis). Exotoxin A, actively secreted from microorganisms such as Pseudomonas aeruginosa, binds to the low-density receptor protein on monocytes and inhibits both cytokine and protein synthesis (21). Exotoxin A fragments, however, are able to induce cytokine production in mononuclear cells (19).

Dialysate contaminants of microbial origin, such as endotoxin, can unequivocally induce IL-1 and TNF synthesis and secretion. Endotoxin monomers, low molecular weight substances derived from dialysate-borne bacteria or certain LPS fragments, can permeate across dialysis membranes and stimulate cytokine production by monocytes. Activated monocytes may sequester in the lung and transit into tissue as macrophages with potential pathologic sequelae (22). LPS (molecular weight >100 kD), peptidoglycans (molecular weight >20 kD), or endotoxin A (molecular weight 71 kD) are not able to penetrate low-flux dialyzer membranes. In contrast, small fragments of bacterial products with cytokine-inducing activity present in contaminated dialysate may penetrate dialyzer membranes. Pyrogen permeability of dialyzer membranes depends on membrane thickness, hydrophobic domains, charge, and protein adsorption. Synthetic dialyzer membranes such as polysulfone and polyamide have reduced pyrogen permeability because of their thickness and their ability to adsorb pyrogens either by hydrophobic membrane domains or by plasma proteins coating the membrane surface (19).

IL-1 receptor antagonist (IL-1RA) can reduce or block the ability of IL-1 to activate cells, whereas soluble TNF receptor can reduce or block the activity of TNF (22). In this study, 32.6% of the hemodialysis patients were found to present with anti-IL-1{alpha} autoantibodies, but only 1.4% of healthy subjects did so. These autoantibodies have a neutralizing effect on IL-1{alpha}, at least in vitro. In contrast, IL-6 autoantibodies detectable in 18.2% of hemodialysis patients were not found to influence IL-6-dependent proliferation of B9 cells (23,24). The endogenous synthesis of IL-1RA is a reliable marker of the level of IL-1ß synthesis in hemodialysis patients. On the other hand, the diminished endotoxin- or IgG-stimulated IL-1RA synthesis with increasing time on dialysis is possibly another sign of the impaired host defense system in patients on long-term hemodialysis (25).

Patient Outcomes
Hemodialysis hypotension has been linked to IL-1 production during hemodialysis treatment (26). A symptomatic fall in BP may be caused by a net ultrafiltration rate exceeding the vascular refilling rate or by the use of acetate resulting in a vasodilatory action on the microvascular resistance vessels. Furthermore, an autonomic nervous system neuropathy of the afferent limb of the carotid and aortic baroreflex arc that blunts or blocks the normal vasoconstrictor or cardioaccelerator response to vascular volume depletion may be responsible for hemodialysis associated hypotension. BP fall may also be caused by bioincompatibility of the cuprophane membrane, releasing the anaphylatoxins C3a and C5a. Finally, the lower the body temperature that occurs during treatment with hemodiafiltration, the better the hemodynamic stability. IL-1 is produced during hemodialysis by either or both of two mechanisms: stimulation of monocytes and induction of IL-1 secretion by the binding of C5a to monocyte surface, particularly during hemodialysis with bioincompatible membranes; and stimulation of monocytes adsorbed to the blood side of the dialysis membrane by dialysate-derived exogenous pyrogenic materials (26).

This suggestion, however, is based on experimental data. The findings of these animal studies should not automatically be extended to humans. The difference in incidence of symptomatic hypotension between hemofiltration and hemodialysis could be explained by the following: (1) the reduced capacity of the noncellulosic membranes used for hemofiltration to activate complement; (2) the lack of exogenous pyrogenic substances in the dialysate of patients undergoing hemofiltration; and (3) the lower body temperature associated with low-monocyte-mediated IL-1 production during hemodiafiltration (because monocytes are believed to be sensitive to clinically relevant changes of temperature) (26).

Several studies have shown that lowering of temperature in the extracorporeal circuit causes BP stabilization. The lack of exogenous pyrogenic substances in the dialysate of hemofiltration patients is also an important factor reducing symptomatic hypotension.

Kimmel et al. (27) performed a prospective cross-sectional, observational multicenter study of 230 urban hemodialysis patients to determine the contribution of immunologic factors to patient survival. It was found that higher levels of circulating proinflammatory cytokines such as IL-1, TNF-{alpha}, IL-6, and IL-13 are associated with mortality, whereas IL-2, IL-4, IL-12, and immune parameters reflecting improved T cell function are associated with survival in patients with ESRD treated with hemodialysis, independent of other medical risk factors.

Neutrophils
There are numerous blood parameters that may be used to evaluate biocompatibility of dialysis membranes. The potential of different dialyzers to produce cytokines has been discussed above. The following discussion will focus on neutrophil parameters and their relevance to determine membrane biocompatibility.

Complement Activation and Neutropenia
Hemodialysis with cuprophane membranes produces a transient, severe neutropenia during the first half hour (28). In vitro and in vivo data have shown that this effect is dependent on complement activation via the alternative complement pathway (29,30). The activated neutrophils migrate to the lungs, resulting in mild pulmonary dysfunction during hemodialysis, particularly if dialysate containing acetate was used. Measurement of plasma C3a during routine hemodialysis with cuprophane membranes showed early (10 to 15 min) and striking (6000 ng/ml) elevations of this anaphylatoxin occurring in the venous line from the dialyzer. There is a strong correlation between hemodialysis leukopenia and complement activation as measured by the release of C3a during the first 30 min of treatment (31). Complement activation has been shown to increase the adhesivenesss of granulocytes for a variety of foreign surfaces (32–34). Furthermore, both activated granulocytes and platelets share the ability to aggregate, arriving in the lung by microembolization (35). Less complement-activating membranes such as polysulfone (36), polyacrylonitrile (37) or cellulose acetate (38) are associated with less neutropenia and less hypoxemia. Reused dialyzers also lead to less complement activation than do fresh ones as a result of fixation of plasma proteins to the dialyzer membrane (39,40).

Reversal of granulocytopenia during hemodialysis with cellulosic membranes has been attributed to some or all of the following: selective downregulation of C5a complement receptors on PMNL; internalization of C5a complement receptors on granulocytes (41); and reduction of plasma C5a concentration below the critical threshold needed for granulocyte-endothelial cell adhesion.

Adhesion of neutrophils stimulated by C5a complement to endothelial cells is transient (42). Himmelfarb et al. (43) found, however, that the C5a receptor number does not significantly change during cuprophane hemodialysis, suggesting that this mechanism is not important. Complement activation by the dialysis membrane may cause an increase in the expression of the ß2-integrin receptors (42,44–47). These activated cells will aggregate and adhere to the pulmonary endothelium (48). Synthetic membranes generally induce markedly less complement activation and also reduce the upregulation of adhesion receptors compared with cuprophane membranes (49).

Phagocyte Function and Oxygen Species Production
Phagocyte function is suppressed during dialysis with complement-activating cuprophane (50,51). In contrast, PMNL activity is unaltered during hemodialysis with other, non-complement-activating dialyzer membranes. In prospective studies, Vanholder et al. (52) and Vanholder and Ringoir (53) found that during the first 12 wk after starting hemodialysis, the glycolytic response and reactive oxygen production were substantially lower in patients treated with cuprophane when compared with those who underwent dialysis with polysulfone membranes. It was concluded that complement activation by cuprophane suppresses phagocytotic response both acutely and chronically. Himmelfarb et al. (43,54,55) found less granulocyte oxygen species production in response to Staphylococcus aureus during hemodialysis with complement-activating membranes compared with non-complement-activating membranes. Rosenkranz et al. (56) observed significantly higher production of reactive oxygen intermediates by PMNL during hemodialysis with cuprophane as compared with polysulfone membranes. There are reports from several other groups that show both suppression and enhancement of neutrophil oxygen radical production (57,58).

Upregulation of Specific Cell Surface Receptor Proteins
Upregulation of specific cell surface receptor proteins such as CR1 (59) and Mac-1 (60) and downmodulation of the selectin LAM-1 (61) and sialophorin (CD43) have been reported during hemodialysis with cellulosic membranes (62). In contrast, hemodialysis treatment of the same patients with biocompatible non-complement-activation membranes results in only mild granulocytopenia and no significant changes in receptor expression. Complement split products are responsible for the up- and downregulation of neutrophil integrins and selectins (61).

Tielemans et al. (63) evaluated the expression of CD11b (Mac-1, CR3, or C3bi receptor), CD11a (leukocyte function antigen 1 or LFA-1, or gp 180/95), CD54 (intracellular adhesion molecule 1 or ICAM-1), and CD45 (leukocyte common antigen) on circulating leukocytes. Hemodialysis treatment with cuprophane or cellulose acetate membranes was associated with upregulation of CD11b and CD45, confirming the previous data of Arnaout et al. (60). The magnitude of CD11b expression was similar to in vitro expression induced by incubation with C5a desarg. In contrast, hemodialysis treatment with reused cuprophane membranes is not associated with complement activation and did not upregulate CD11b on PMNL (60). Increased Mac-1 expression after 15 min of hemodialysis with a cuprophane membrane has also been reported by Thylén et al. (47). Expression of Mac-1 remained stable during polysulfone hemodialysis (64). Surface expression of L-selectins of granulocytes was found to decrease rapidly during the initial phase of cuprophane hemodialysis and then recover after 3 h to levels observed before starting hemodialysis. In contrast, the surface expression of L-selectins on granulocytes during the first 15 min of polysulfone hemodialysis was unchanged (64). A study by Mrowka et al. (65) suggested that the level of circulating adhesion molecules does not serve as an appropriate marker of membrane biocompatibility.

Selectins are responsible for the initial "rolling" interaction of leukocytes with the vascular endothelium (66), whereas firm adhesion of leukocytes to endothelial cells is dependent on the ß2-integrins (67). Low L-selectin and high Mac-1 expression on granulocytes occurring during cuprophane hemodialysis lead to a decreased ratio between L-selectin and Mac-1 on granulocytes. This could impair the host defense of hemodialysis patients, particularly when cellulosic dialysis membranes are used (64).

Rosenkranz et al. (68) evaluated the contribution of reactive oxygen intermediate formation for receptor modulation by the cuprophane membrane on neutrophils. In patients who underwent dialysis with cuprophane, CD11b and CD66b upregulation of neutrophils and L-selectin downregulation was seen. The expression of CD11a remained unaltered. Hemodialysis with polysulfone did not change the surface receptor expression. Similar results were obtained during in vitro incubation of isolated neutrophils with cuprophane or polysulfone in the presence of serum. Generation of reactive oxygen intermediates by cuprophane occurred in the absence of serum. A novel C5-dependent neutrophil-activating mechanism, probably attributable to the release of oxygen radicals in addition to the expected complement activation, was found (68).

Degranulation
Neutrophil degranulation occurs during hemodialysis (69). This process, however, is not dependent on complement activation. For example, hemodialysis therapy with PMMA membranes results in only mild complement activation compared with cuprophane. Degranulation of neutrophils, however, is as pronounced with PMMA as with cuprophane (70). Reuse of cuprophane membranes considerably reduces complement levels but fails to affect degranulation of secondary granules (71). It has been shown that low doses of heparin may result in clot formation within the dialyzer and enhance complement formation, but neutrophil degranulation does not increase (72). Degranulation of neutrophils during hemodialysis depends on intracellular calcium and the presence or absence of degranulation-inhibiting proteins. Calcium channel blockers reduce cytosolic calcium and neutrophil degranulation during dialysis (73) and during aortocoronary bypass operation (74), even in the presence of complement activation. Extracorporeal calcium depletion during regional citrate anticoagulation abolishes lactoferrin (75) or myeloperoxidase (76) release. The mechanisms for the change in intracellular calcium that leads to degranulation are unclear.

Two neutrophil degranulation-inhibiting proteins identified as angiogenin (77) and complement factor D (78) have been described. Both proteins are markedly elevated in plasma of patients with ESRD. During hemodialysis with low-flux dialysis membranes, neither plasma levels of angiogenin nor complement factor D are altered. Under these conditions, there is only a mild release of lactoferrin from neutrophils. Surprisingly, hemodialysis with PMMA or polyacrylonitrile results in marked lactoferrin release (73,79). This is explained by the fact that both high-flux dialyzers cause a striking reduction of both plasma angiogenin (80) and complement factor D (81,82). This is a novel mechanism explaining neutrophil degranulation during extracorporeal circulation (80). Both PMNL degranulation inhibitors are markedly elevated in the plasma of patients with ESRD.

Table 1 shows the differences between polysulfone and polyacrylonitrile with respect to angiogenin and complement factor D reduction. AN69 reduced plasma angiogenin level to 34.4% of the predialysis values and factor D level to 72.5% during hemodialysis, whereas polysulfone reduced plasma angiogenin to 64.1% and did not change complement factor D level. These data demonstrate that endogenous PMNL inhibitors such as angiogenin and complement factor D must be considered if neutrophil activation parameters were measured to investigate bioincompatibility of dialyzer membrane materials. However, there must be more to this process than just removal of degranulation inhibitory proteins; otherwise, there would not be degranulation with low-flux cellulose membranes.


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  		Table 1. Effect of polysulfone (F60) and polyacrylonitrile (AN69) on plasma angiogenin and complement factor D levels in patients on maintenance hemodialysisa
 
Apoptosis
Cendoroglo et al. (83) investigated the contribution of apoptosis to neurophil dysfunction in uremia. Compared with normal neutrophils, uremic neutrophils demonstrated greater apoptosis in the presence of autologous plasma as well as 10% fetal calf serum. Furthermore, compared with normal neutrophils exposed to heterologous normal plasma, those exposed to heterologous uremic plasma exhibited higher apoptosis rates, lower N-formyl methionyl-leucyl-phenylalanine-stimulated superoxide production, and a lower phagocytosis index. Apoptosis correlated inversely with N-formyl methionyl-leucyl-phenylalanine-stimulated superoxide production. It was concluded that uremic neutrophils undergo accelerated apoptosis in vitro. The authors also demonstrated that uremic plasma accelerates apoptosis of normal neutrophils, resulting in a dysfunctional pattern that is similar to that observed in uremia (83).

Martin-Malo et al. (84) evaluated the effect of both uremia per se and hemodialysis membranes on the induction of apoptosis. Cell apoptosis was higher in hemophane than the other hemodialysis membranes. Moreover, apoptosis decreased in hemodialysis patients after they switched from hemophane to polysulfone. Mononuclear cell circulation through minidialyzers made of different types of membranes (cuprophane, hemophane, cellulose acetate, polyacrylonitrile, and polysulfone) produced a significant increase in apoptosis when hemophane or cuprophane were used, as compared with the other three membranes. Uremia and membrane characteristics might independently affect the mononuclear cell apoptosis (84).

Cohen et al. (85) found that PMNL apoptosis increases in the presence of glucose-modified serum proteins. Early glycation of proteins, as analyzed by boronate chromatography and the fructosamine assay, is responsible for the increase of PMNL apoptosis. In addition, early glycated proteins, isolated by preparative boronate chromatography from the effluent of chronic ambulatory peritoneal dialysis patients, increased PMNL apoptosis (85). Reduction of glycated proteins by high-flux dialyzers either via adsorption or convection may improve PMNL apoptosis in vivo.

Recently Cohen et al. (86) investigated the influence of isolated free Ig light chains (IgLC) and of commercially available IgLC on spontaneous PMNL apoptosis. IgLC of both kappa and lambda type were able to increase the percentage of viable PMNL by inhibiting spontaneous apoptosis in a concentration-dependent manner. IgLC, elevated in plasma of patients with ESRD, could interfere with the normal resolution of inflammation and thereby contribute to the chronic inflammatory state found in dialysis patients.

Middle Molecules
Clinical signs and symptoms of patients with ESRD are at least in part related to the accumulation of uremic retention solutes and uremic toxins. Middle molecules accumulate as a result of decreased renal function and are the result of oxidative stress, microinflammation, or uremia per se, leading to protein modifications that may cause new biologic functions. Middle molecules include the following: parathyroid hormone; ß2-microglobulin; advanced glycation end products (AGE); advanced lipoxidation end products; advanced oxidation protein products; granulocyte inhibitory proteins; and leptin.

Parathyroid Hormone
Parathyroid hormone has been identified as an uremic toxin. Parathyroid hormone increases in patients with ESRD as a result of enhanced glandular secretion and not as a result of decreased renal function. Excess parathyroid hormone causes a rise in intracellular calcium, disturbing the functions of virtually every organ system, including bone mineralization, pancreatic response to metabolic and hormonal changes, erythropoiesis, the immune system, the heart, the liver, or the brain (87). Increased cellular calcium results in PMNL deactivation (88,89), which can be normalized by calcium channel blockers (90).

ß2-Microglobulin
Dialysis-related amyloid is to a large extent composed of ß2-microglobulin (ß2M). The clinical picture of dialysis-related amyloidosis (DRA) include (91) the following: carpal tunnel syndrome; chronic invalidating arthralgias; multiple bone cysts; bone fractures; spinal cord compressions; and gastrointestinal complications (bleeding, perforation). A third of the patients are affected by DRA before 4 yr, and more than 90% are affected after more than 7 yr on hemodialysis treatment. Risk factors for the development of DRA include the following: contamination of the dialysate; age of the patient at onset of dialysis; type of hemodialysis membrane; and time on dialysis.

Protective effect of high-flux membranes such as AN69 or polysulfone with respect to DRA results mainly from the effective reduction of ß2M via adsorption, convection, or both. Residual renal function may also play a role in ß2M removal. The lowest incidence of DRA has been observed when ultrapure dialysate is used (92).

Numerous studies have been performed demonstrating lower manifestation of DRA in patients on long-term treatment with biocompatible membrane materials as compared with cuprophane. For example, van Ypersele et al. (93), who used carefully defined criteria for radiologic amyloid bone cysts, found significantly more amyloid bone cysts in cuprophane-treated patients as compared with patients undergoing regular hemodialysis treatment with the AN69 membrane. Hakim et al. (94) randomly assigned 159 patients starting hemodialysis to either a low-flux bioincompatible cellulosic membrane or a low-flux biocompatible PMMA membrane. Sixty-six patients completed the 18-mo study. Despite a similar progressive reduction of residual renal function in both groups, serum ß2M level increased by an average of 11.8 mg/L in the cellulosic group (P < 0.0001). There was, however, no significant increase of ß2M in the PMMA group during the study period of 18 mo. Bioincompatibility of the cuprophane membrane causes either stimulation of synthesis or release ß2M (89). Data of Matsuo et al. (95) provided the first evidence for the presence of TGF-ß in DRA tissue, as well as the stimulatory action of AGE-ß2M on tissue macrophages.

Advanced AGE
Irreversible nonenzymatic modification of proteins occurs in chronic renal failure. Proteins exposed to glucose or other carbohydrates form advanced AGE. AGE accumulate as a result of impaired renal excretion. Elevated AGE concentrations have been reported in the tissues and plasma of patients with diabetes and patients with chronic renal failure (96,97). These end products account for numerous biologic responses (98) and also promote the release of cytokines (99). For example, Miyata et al. (100) provided evidence that ß2M modified by advanced AGE is a dominant constituent of these amyloid deposits and increases the secretion of TNF-{alpha} and IL-1ß from macrophages, whereas normal ß2M had no effect (101). High-flux hemodialysis markedly reduced low molecular weight AGE-modified molecules (by 47.9% in patients with diabetes and 60.6% in dialysis patients without diabetes), but concentrations returned to the pretreatment range within 3 h (102).

Specific methods have been developed to quantify AGE such as pentosidine or carboxymethyllysine (103,104). It has been shown that pentosidine and carboxymethyllysine are significantly higher in plasma and tissue proteins of hemodialysis patients compared with healthy subjects (105,106). In uremia, however, neither of these AGE correlate with fructoselysine, suggesting that factors other than hyperglycemia are responsible for the rate of AGE formation.

Advanced Lipoxidation End Products
Malondialdehyde-modified proteins also accumulate in the plasma of patients with ESRD. Malondialdehyde is derived from the oxidation of polyunsaturated fatty acids. The malondialdehyde and other lipid modified proteins are called "advanced lipidoxidation end products" (107).

Formation of AGE and advanced lipoxidation end products occurs between proteins and reactive carbonyl compounds derived from carbohydrates and lipids; their production in uremia is mainly the result of oxidative stress and decreased renal clearance (108). Residual renal function influences the pentosidine level in uremic patients (109,110). It has been suggested that the "carbonyl stress" is associated with long-term complications of patients with ESRD, such as dialysis-related amyloidosis or atherosclerosis (108).

Advanced Oxidation Protein Products
Changes in cell surface receptor expression occur in uremia by activated phagocytes or interaction of white blood cells with bioincompatible dialysis membranes (45–47,57,111). In addition, uremia causes oxidant-mediated protein alterations (112–114). Furthermore, these patients have a severe defect in antioxidant enzyme activity, antioxidant enzyme cofactors, and antioxidant vitamins.

Protein damage mediated by reactive oxygen species results in oxidation of amino acid residues such as tyrosine. When di-tyrosine is formed, protein aggregation, cross-linking, and fragmentation occurs. These di-tyrosine-containing, cross-linked protein products were designated "advanced oxidation protein products" (AOPP) (112,113). AOPP were found in very high concentrations in the plasma of dialysis patients. Because patients treated with peritoneal dialysis and patients experiencing preterminal renal failure also have significantly higher AOPP levels than healthy subjects, it was concluded that uremia per se induces a significant oxidative stress (112,113). The accumulation of AOPP starts at an early stage of chronic renal failure and gradually rises with the progression of renal failure. There is an inverse relationship between AOPP levels and creatinine clearance. A close relationship between AOPP and AGE-pentosidine has been observed. Human serum albumin exposed to chlorinated oxidants (HOCl) resulted in AOPP-human serum albumin formation. Myeloperoxidase released during hemodialysis is a major factor contributing to AOPP formation. Myeloperoxidase and chlorinated oxidant-induced lipoprotein by-products are present in atherosclerotic lesions (115,116). These data suggest that AOPP may play a role in the development of atherosclerosis (117). It has been shown that regional citrate anticoagulation prevents PMNL degranulation (75) and myeloperoxidase release (76). Therefore, it would be interesting to investigate whether regional citrate anticoagulation reduces AOPP formation.

Granulocyte Inhibitory Proteins
Low molecular weight uremic toxins that inhibit neutrophil functions include p-cresol (118) and several guanidino compounds (119). It has been shown that uremic neutrophils undergo accelerated apoptosis (83,84). AGE-modified serum proteins have been identified as uremic toxins that accelerate PMNL apoptosis, at least in vitro (85), whereas light chain proteins inhibit PMNL apoptosis (86).

Several peptides accumulate in renal failure and interfere with specific cellular functions, as follows:

The presence of granulocyte inhibitory proteins of middle molecular weight in the plasma of patients with ESRD holds promise of explaining the common occurrence of hospitalization and death by infection in this population.

Leptin
Uremic patients have elevated serum leptin that accumulates with the decrease of renal function. Renal transplantation normalizes plasma leptin levels (124). Men with normal body-mass index and low plasma insulin levels, however, have normal or even low leptin levels despite renal insufficiency (125). It has been shown that nonrenal tissues such as splanchnic organs contribute substantially to the removal of leptin (126). Ob gene expression in uremic patients is lower than in controls (127). Leptin mRNA expression is stimulated by increased body fat mass and hyperinsulinemia in nonuremic subjects and in uremic patients. Molecular studies of leptin for renal disease patients and the possible link between leptin and BP have been reviewed (128,129).

Conclusion

Enhanced production of proinflammatory cytokines by dialysate pyrogens, by complement activation, or both, as well as inhibition of anti-inflammatory cytokine secretion, may contribute to the cell-mediated immunosuppression seen in patients with ESRD. Furthermore, multiple alterations of neutrophils occur as a result of uremia per se and bioincompatible dialyzer membranes. The presence of low and high molecular weight inhibitors of neutrophils in the plasma of uremic patients may explain, at least in part, why infections are the most common cause of hospitalization and the second most common cause of death in patients with ESRD. Other middle molecules accumulate, and proteins are modified by oxidative stress, carbonyl stress, or both, contributing to the uremic syndrome. To lower these toxic substances, either their generation should be reduced or strategies for effective removal should be developed.

References

  1. Bingel M, Lonnemann G, Koch KM, Dinarello CA, Shaldon S: Plasma interleukin-1 activity during hemodialysis: The influence of dialysis membranes. Nephron 50: 273–276, 1988[Medline]
  2. Descamps-Latscha B, Herbelin A, Nguyen AT, Uzan M, Zingraff J: Haemodialysis-membrane-induced phagocyte oxidative metabolism activation and interleukin-1 production. Life Support Syst 4: 349–353, 1986[Medline]
  3. Herbelin A, Nguyen AT, Zingraff J, Urena P, Descamps-Latscha B: Influence of uremia and hemodialysis on circulating interleukin-1 and tumor necrosis factor. Kidney Int 37: 116–125, 1990[Medline]
  4. Lonnemann G, Bingel M, Koch KM, Shaldon S, Dinarello CA: Plasma interleukin-1 activity in humans undergoing hemodialysis with regenerated cellulosic membranes. Lymphokine Res 6: 63–70, 1987[Medline]
  5. Luger A, Kovarik J, Stummvoll HK, Urbanska A, Luger T: Blood-membrane interaction in hemodialysis leads to increased cytokine production. Kidney Int 32: 84–88, 1987[Medline]
  6. Girndt M, Heisel O, Köhler H: Influence of dialysis with polyamide vs haemophan haemodialysers on monokines and complement activation during a 4-month long-term study. Nephrol Dial Transplant 14: 676–682, 1999[Abstract/Free Full Text]
  7. Pereira BJG, Dinarello CA: Production of cytokines and cytokine inhibitory proteins in patients on dialysis. Nephrol Dial Transplant 9 [Suppl 2]: 60–71, 1994[Abstract/Free Full Text]
  8. Blumenstein M, Schmidt B, Ward RA: Altered interleukin-1 production in patients undergoing hemodialysis. Nephron 50: 277–281, 1988[Medline]
  9. Haeffner-Cavaillon N, Cavaillon JM, Ciancioni C: In vivo induction of interleukin-1 during hemodialysis. Kidney Int 35: 1212–1218, 1989[Medline]
  10. Lonnemann G, Haubitz M, Schindler R: Hemodialysis-associated induction of cytokines. Blood Purif 8: 214–222, 1990[CrossRef][Medline]
  11. Lonnemann G, Van den Meer JWM, Cannon JG, Dinarello CA, Koch KM, Granolleras C, Deschodt G, Shaldon S: Induction of tumor necrosis factor during extracorporeal blood purification. N Engl J Med 317: 963–964, 1987[Medline]
  12. Le Meur Y, Lorgeot V, Aldigier J-C, Wijdenes J, Leroux-Robert C, Praloran V: Whole blood production of monocytic cytokines (IL-1ß, IL-6, TNF-{alpha}, sIL- 6R, IL- 1Ra) in haemodialysed patients. Nephrol Dial Transplant 14: 2420–2426, 1999[Abstract/Free Full Text]
  13. Schindler R, Linnenweber S, Schulze M, Oppermann M, Dinarello CA, Shaldon S, Koch KM: Gene expression of interleukin-1ß during hemodialysis. Kidney Int 43: 712–721, 1993[Medline]
  14. Schindler R, Lonnemann G, Shaldon S, Koch KM, Dinarello CA: Transcription, not synthesis, of interleukin-1 and tumor necrosis factor by complement. Kidney Int 37: 85–93, 1990[Medline]
  15. Haeffner CN, Cavaillon JM, Laude M, Kazatchkine MD: C3a (C3adesArg) induces production and release of interleukin 1 by cultured human monocytes. J Immunol 139: 794–799, 1987[Abstract]
  16. Okusawa S, Dinarello CA, Yancey KB, Endres S, Lawley TJ, Frank MM, Burke JF, Gelfand JA: C5a induction of human interleukin 1. Synergistic effect with endotoxin or interferon-gamma. J Immunol 139: 2635–2640, 1987[Abstract]
  17. Memoli B, Marzano L, Bisesti V, Andreucci M, Guida B: Hemodialysis-related lymphomononuclear release of interleukin-12 in patients with end-stage renal disease. J Am Soc Nephrol 10: 2171–2176, 1999[Abstract/Free Full Text]
  18. Girndt M, Lengler S, Kaul H, Sester U, Sester M, Köhler H: Prospective crossover trial of the influence of vitamin E-coated dialyzer membranes on T-cell activation and cytokine induction. Am J Kidney Dis 35: 95–104, 2000[Medline]
  19. Lonnemann G: Chronic inflammation in hemodialysis: The role of contaminated dialysate. Blood Purif 18: 214–223, 2000[CrossRef][Medline]
  20. Schindler R, Marra MN, McKelligon BM, Lonnemann G, Schulzeck P, Schulze M, Oppermann M, Shaldon S: Plasma levels of bactericidal/permeability-increasing (BPI) and lipopolysaccharide-binding protein (LBP) during hemodialysis. Clin Nephrol 40: 346–351, 1993[Medline]
  21. Staugas RE, Harvey DP, Ferrante A, Nadoskar M, Allison AC: Induction of tumor necrosis factor (TNF) and interleukin-1 (IL-1) by Pseudomonas aeruginosaand exotoxin A-induced suppression of lymphoproliferation and TNF, lymphotoxin, gamma interferon, and IL-1 production in human leukocytes. Infect Immun 60: 3162–3168, 1992[Abstract/Free Full Text]
  22. Colton CK, Ward RA, Shaldon S: Scientific basis for assessment of biocompatibility in extracorporeal blood treatment. Nephrol Dial Transplant 9 [Suppl 2]: 11–17, 1994
  23. Sunder-Plassmann G, Sedlacek PL, Sunder-Plassmann R, Derfler K, Swoboda K, Fabrizii V, Hirschl MM, Balcke P: Anti-interleukin-1{alpha} autoantibodies in hemodialysis patients. Kidney Int 40: 787–791, 1991[Medline]
  24. Sunder-Plassmann G, Kapiotis S, Gasche C, Klaar U: Functional characterization of cytokine autoantibodies in chronic renal failure patients. Kidney Int 45: 1484–1488, 1994[Medline]
  25. Balakrishnan VS, Jaber BL, Natov SN, Cendoroglo M, King AJ, Schmid CH, Pereira BJG: Interleukin-1 receptor antagonist synthesis by peripheral blood mononuclear cells in hemodialysis patients. Kidney Int 54: 2106–2112, 1998[CrossRef][Medline]
  26. Henderson LW, Koch KM, Dinarello CA, Shaldon S: Hemodialysis hypotension: The interleukin hypothesis. Blood Purif 1: 3–8, 1983
  27. Kimmel PL, Phillips TM, Simmens SJ, Peterson RA, Weihs KL, Alleyne S, Cruz I, Yanovski JA, Veis JH: Immunologic function and survival in hemodialysis patients. Kidney Int 54: 236–244, 1998[CrossRef][Medline]
  28. Kaplow LS, Goffinet JA: Profound neutropenia during the early phase of hemodialysis. JAMA 203: 1135–1137, 1968[CrossRef][Medline]
  29. Craddock PR, Fehr J, Dalmasso AP, Brigham KL, Jacob HS: Hemodialysis leukopenia: Pulmonary vascular leukostasis resulting from complement activation by dialyzer cellophane membranes. J Clin Invest 59: 879–888, 1977
  30. Craddock PR, Fehr J, Brigham KL, Kronenberg RS, Jacob HS: Complement- and leukocyte-mediated pulmonary dysfunction in hemodialysis. N Engl J Med 296: 769–774, 1977[Abstract]
  31. Henderson LW, Chenoweth DE: Cellulose membranes—Time for a change? Contrib Nephrol 44: 112–126, 1995
  32. Klock JC, Bainton DF: Degranulation and abnormal bactericide function of granulocytes produced by reversible adhesion to nylon wool. Blood 48: 149–161, 1976[Abstract/Free Full Text]
  33. Tonnesen MG, Smedly LA, Henson PM: Neutrophil-endothelial cell interactions. Modulation of neutrophil adhesiveness by complement fragments C5a and C5a-desarg and formyl-methionyl-leucyl-phenylalanine in vitro. J Clin Invest 74: 1581–1592, 1984
  34. Lentnek AL, Schreiber AD, MacGregor RR: The induction of augmented adherence by inflammation. J Clin Invest 57: 1098–1103, 1976
  35. Craddock PR, Hammerschmidt DE, White JG, Dalmosso AP, Jacob HS: Complement (C5a)-induced granulocyte aggregation in vitro—A possible mechanism of complement-mediated leukostasis and leukopenia. J Clin Invest 60: 260–264, 1977
  36. Hörl WH, Schäfer RM, Heidland A: Effect of different dialyzers on proteinases and proteinase inhibitors during hemodialysis. Am J Nephrol 5: 320–326, 1985[Medline]
  37. Chenoweth DE, Cheung AK, Henderson LW: Anaphylatoxin formation during hemodialysis: Effects of different dialysis membranes. Kidney Int 24: 764–769, 1983[Medline]
  38. Ivanovich P, Chenoweth DE, Schmidt R, Klinkmann H, Boxer LA, Jacob HS, Hammerschmidt DE: Symptoms and activation of granulocytes and complement with two dialysis membranes. Kidney Int 24: 758–763, 1983[Medline]
  39. Chenoweth DE, Cheung AK, Ward DM, Henderson LW: Anaphylatoxin formation during hemodialysis: Comparison of new and re-used dialyzers. Kidney Int 24: 770–774, 1983[Medline]
  40. Stroncek DF, Keshaviah P, Craddock PR, Hammerschmidt DE: Effect of dialyzer re-use on complement activation and neutropenia in hemodialysis. J Lab Clin Med 104: 304–311, 1984[Medline]
  41. Craddock PR, Hammerschmidt DE: Complement mediated granulocyte activation and down-regulation during hemodialysis. ASAIO J 7: 50–56, 1984
  42. Lo SK, Detmers PA, Levin SM, Wright SD: Transient adhesion of neutrophils to endothelium. J Exp Med 169: 1779–1793, 1989[Abstract/Free Full Text]
  43. Himmelfarb J, Gerard NP, Hakim RM: Intradialytic modulation of granulocyte C5a receptors. J Am Soc Nephrol 2: 920–926, 1991[Abstract]
  44. Himmelfarb J, Zaoui P, Hakim R: Modulation of granulocyte LAM-1 and MAC-1 during dialysis—A prospective, randomized controlled trial. Kidney Int 41: 388–395, 1992[Medline]
  45. Alvarez V, Pullido R, Campanero MR, Paraiso V, de Landazuri MO, Sanchez-Madrid F: Differentially regulated cell surface expression of leukocyte adhesion receptors on neutrophils. Kidney Int 40: 899–905, 1991[Medline]
  46. Cheung AK, Parker CJ, Honholt M: Beta2integrins are required for neutrophil degranulation induced by hemodialysis membranes. Kidney Int 43: 649–660, 1993[Medline]
  47. Thylén P, Lundahl J, Fernvik E, Hed J, Svenson SB, Jacobson SH: Mobilization of an intracellular glycoprotein (Mac-1) on monocytes and granulocytes during hemodialysis. Am J Nephrol 12: 393–400, 1992[Medline]
  48. Kolb G, Fischer W, Schoenemann H, Bathke K, Hoffken H, Müller T, Lange H, Joseph K, Havemann K: Effect of Cuprophan, hemophan and polysulfone membranes on the oxidative metabolism, degranulation reaction, enzyme release and pulmonary sequestration of granulocytes. Contrib Nephrol 74: 10–21, 1989[Medline]
  49. Lundahl J, Hed J, Jacobsen SH: Dialysis granulocytopenia is preceded by an increased surface expression of the adhesion-promoting glucoprotein Mac-1. Nephron 61: 163–169, 1992[Medline]
  50. Vanholder R, Ringoir S: Infectious morbidity and defects of phagocytic function in end-stage renal disease: A review. J Am Soc Nephrol 3: 1541–1554, 1993[Abstract]
  51. Ward RA: Phagocytic cell function as an index of biocompatibility. Nephrol Dial Transplant 9 [Suppl 2]: 46–56, 1994
  52. Vanholder R, Ringoir S, Dhondt A, Hakim R: Phagocytosis in uremic and hemodialysis patients: A prospective and cross sectional study. Kidney Int 39: 320–327, 1991[Medline]
  53. Vanholder R, Ringoir S: Polymorphonuclear cell function and infection in dialysis. Kidney Int 42: S91–S95, 1992
  54. Himmelfarb J, Lazarus JM, Hakim RM: Reactive oxygen species production by monocytes and polymorphonuclear leukocytes during hemodialysis. Am J Kidney Dis 17: 271–276, 1991[Medline]
  55. Himmelfarb J, Ault KA, Holbrook D, Leeber DA, Hakim RM: Intradialytic granulocyte reactive oxygen species production: A prospective, crossover trial. J Am Soc Nephrol 4: 178–186, 1993[Abstract]
  56. Rosenkranz AR, Templ E, Traindl O, Heinzl H, Zlabinger GJ: Reactive oxygen product formation by human neutrophils as an early marker for biocompatibility of dialysis membranes. Clin Exp Immunol 98: 300–305, 1994[Medline]
  57. Nguyen AT, Lethias C, Zingraff, Herbelin A, Naret C, Descamps-Latscha B: Hemodialysis membrane-induced activation of phagocyte oxidative metabolism detected in vivo and in vitro within microamounts of whole blood. Kidney Int 28: 158–167, 1985[Medline]
  58. Cristol JP, Canaud B, Rabesandratana H, Gaillard I, Serre A, Mion C: Enhancement of reactive oxygen species production and cell surface markers expression due to haemodialysis. Nephrol Dial Transplant 9: 389–394, 1994[Abstract/Free Full Text]
  59. Lee J, Hakim RM, Fearon DT: Increased expression of the C3b receptor by neutrophils and complement activation during hemodialysis. Clin Exp Immunol 56: 205–214, 1984[Medline]
  60. Arnaout 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[Abstract]
  61. Himmelfarb J, Zaoui P, Hakim RM: Modulation of granulocyte LAM-1 and Mac-1 during dialysis: A prospective, randomized controlled trial. Kidney Int 41: 388–398, 1992
  62. Alvarez V, Pulido R, Campanero MR, Paraiso V, De Landzuri MO, Sunchez-Madrid F: Differentially regulated cell surface expression of leukocyte adhesion receptors on neutrophils. Kidney Int 40: 899–905, 1991
  63. Tielemans CL, Delville JPC, Husson CP, Madhoun P, Lambrechts AM, Goldman M, Vanherweghem JL: Adhesion molecules and leukocyte common antigen on monocytes and granulocytes during hemodialysis. Clin Nephrol 39: 158–165, 1993[Medline]
  64. Thylén P, Fernvik E, Lundahl J, Hed J, Jacobson SH: Cell surface receptor modulation on monocytes and granulocytes during clinical and experimental hemodialysis. Am J Nephrol 15: 392–400, 1995[Medline]
  65. Mrowka C, Heintz B, Sieberth H-G: Is dialysis membrane type responsible for increased circulating adhesion molecules during chronic hemodialysis? Clin Nephrol 52: 312–321, 1999[Medline]
  66. Lawrence MB, Springer TA: Leukocytes roll on a selectin at physiologic flow rates. Distinction from and prerequisite for adhesion through integrins. Cell 65: 859–873, 1991[CrossRef][Medline]
  67. Springer TA: Adhesion receptors of the immune system. Nature 346: 425–434, 1990[CrossRef][Medline]
  68. Rosenkranz AR, Körmöczi GF, Thalhammer F, Menzel EJ, Hörl WH, Mayer G, Zlabinger GJ: Novel C5-dependent mechanism of neutrophil stimulation by bioincompatible dialyzer membranes. J Am Soc Nephrol 10: 128–135, 1999[Abstract/Free Full Text]
  69. Hörl WH, Steinhauer HB, Schollmeyer P: Plasma levels of granulocyte elastase during hemodialysis: Effects of different dialyzer membranes. Kidney Int 28: 791–796, 1985[Medline]
  70. Hörl WH, Riegel W, Schollmeyer P, Rautenberg W, Neumann S: Different complement and granulocyte activation in patients dialyzed with PMMA dialyzers. Clin Nephrol 25: 304–307, 1986[Medline]
  71. Hörl WH, Feinstein EI, Wanner C, Frischmuth N, Gösele A, Massry SG: Plasma levels of main granulocyte components during hemodialysis. Comparison of new and reused dialyzers. Am J Nephrol 10: 53–57, 1990[Medline]
  72. Cheung AK, Faezi-Jenkin B, Leypoldt JK: Effect of thrombosis on complement activation and neutrophil degranulation during in vitro hemodialysis. J Am Soc Nephrol 5: 110–115, 1994[Abstract]
  73. Haag-Weber M, Schollmeyer P, Hörl WH: Granulocyte activation during haemodialysis in the absence of complement activation: Inhibition by calcium channel blockers. Eur J Clin Invest 18: 380–385, 1988[Medline]
  74. Riegel W, Spillner G, Schlosser V, Hörl WH: Plasma levels of main granulocyte components during cardiopulmonary bypass. J Thorac Cardiovasc Surg 95: 1014–1019, 1988[Abstract]
  75. Böhler J, Schollmeyer P, Dressel B, Dobos G, Hörl WH: Reduction of granulocyte activation during hemodialysis with regional citrate anticoagulation: Dissociation of complement activation and neutropenia from neutrophil degranulation. J Am Soc Nephrol 7: 234–241, 1996[Abstract]
  76. Bos JC, Grooteman MPC, van Houte AJ, Schoorl M, van Limbeck J, Nubé MJ: Low polymorphonuclear cell degranulation during citrate anticoagulation: A comparison between citrate and heparin dialysis. Nephrol Dial Transplant 12: 1387–1393, 1997[Abstract/Free Full Text]
  77. Tschesche H, Kopp C, Hörl WH, Hempelmann U: Inhibition of degranulation of polymorphonuclear leukocytes by angiogenin and its tryptic fragment. J Biol Chem 269: 30274–30280, 1994[Abstract/Free Full Text]
  78. Balke N, Holtkamp U, Hörl WH, Tschesche H: Inhibition of degranulation of human polymorphonuclear leukocytes by complement factor D. FEBS Lett 371: 300–302, 1995[CrossRef][Medline]
  79. Haag-Weber M, Poppek C, Ranucht H, Schollmeyer P, Hörl WH: Effect of calcium channel blockers on granulocyte activation during hemodialysis. Contrib Nephrol 74: 106–112, 1989[Medline]
  80. Schmaldienst S, Hörl WH: Degranulation of polymorphonuclear leukocytes by dialysis membranes—The mystery clears up? Nephrol Dial Transplant 15: 1909,1910., 2000[Free Full Text]
  81. Pasqual M, Schifferli JA: Adsorption of complement factor D by polyacrylonitrile dialysis membranes. Kidney Int 43: 903–911, 1993[Medline]
  82. Pasqual M, Schifferli JA, Pannatier JG, Wauters JP: Removal of complement factor D by adsorption on polymethylmethacrylate dialysis membranes. Nephrol Dial Transplant 8: 1305–1306, 1993[Free Full Text]
  83. Cendoroglo M, Jaber BL, Balakrishnan VS, Perianayagam M, King AJ, Pereira BJG: Neutrophil apoptosis and dysfunction in uremia. J Am Soc Nephrol 10: 93–100, 1999[Abstract/Free Full Text]
  84. Martin-Malo A, Carracedo J, Ramirez R, Rodriguez-Benot A, Soriano S, Rodriguez M, Aljama P: Effect of uremia and dialysis modallity on mononuclear cell apoptosis. J Am Soc Nephrol 11: 936–942, 2000[Abstract/Free Full Text]
  85. Cohen G, Rudnicki M, Walter F, Niwa T, Hörl WH: Glucose-modified proteins modulate essential functions and apoptosis of polymorphonuclear leukocytes. J Am Soc Nephrol 12: 1264–1271, 2001[Abstract/Free Full Text]
  86. Cohen G, Rudnicki M, Hörl WH: Uremic toxins modulate the spontaneous apoptotic cell death and essential functions of neutrophils. Kidney Int 59 (suppl 78): S48–S52, 2001[CrossRef]
  87. Massry SG, Smogorzweski M: Mechanisms through which parathyroid hormone mediates its deleterious effects on organ function in uremia. Semin Nephrol 14: 219–231, 1994[Medline]
  88. Alexiewicz JM, Smogorzewski M, Fadda GZ, Massry SG: Impaired phagocytosis in dialysis patients: Studies on mechanisms. Am J Nephrol 11: 102–111, 1991[Medline]
  89. Wenisch C, Patruta S, Daxböck F, Krause R, Hörl WH: Effect of age on human neutrophil function. J Leukoc Biol 67: 40–45, 2000[Abstract]
  90. Hörl WH, Haag-Weber M, Mai B, Massry SG: Verapamil reverses abnormal [Ca2+]i and carbohydrate metabolism of PMNL of dialysis patients. Kidney Int 47: 1741–1745, 1995[Medline]
  91. Jadoul M: Dialysis-related amyloidosis: Importance of biocompatibility and age. Nephrol Dial Transplant 13 (suppl 7): 61–64, 1998[Abstract/Free Full Text]
  92. Lonnemann G, Koch KM: Beta2-microglobulin amyloidosis: Effects of ultra-pure dialysate and type of dialyzer membrane. J Am Soc Nephrol 13 (suppl 1): S72–S77, 2001[Abstract/Free Full Text]
  93. van Ypersele de Strihou C, Jadoul M, Malghem J, Maldague B, Jamart J, and the Working Party on Dialysis Amyloidosis: Effect of dialysis membrane and patient’s age on signs of dialysis-related amyloidosis. Kidney Int 39: 1012–1019, 1991[Medline]
  94. Hakim RM, Wingard RL, Husni L, Parker RA, Parker TFIII: The effect of membrane biocompatibility on plasma ß2-microglobulin levels in chronic hemodialysis patients. J Am Soc Nephrol 7: 472–478, 1996[Abstract]
  95. Matsuo K, Ikizler TA, Hoover RL, Nakamoto M, Yasunaga C, Pupim LB, Hakim RM: Transforming growth factor-beta is involved in the pathogenesis of dialysis-related amyloidosis. Kidney Int 57: 697–708, 2000[Medline]
  96. Sell DR, Monnier VW: End-stage renal disease and diabetes catalyze the formation of a pentose-derived crosslink from aging human collagen. J Clin Invest 85: 380–384, 1990
  97. Makita Z, Radoff S, Rayfied EJ, Yang Z, Skolink E, Delaney V, Friedman EA, Cerami A, Vlassara H: Advanced glycosylation end products in patients with diabetic nephropathy. N Engl J Med 325: 836–842, 1991[Abstract]
  98. Vlassara H, Bucala R, Striker L: Pathogenic effects of advanced glycosylation; biochemical, biologic, and clinical implications for diabetes and aging. J Lab Invest 70: 138–151, 1994[Medline]
  99. Vlassara H, Brownlee M, Manogue KR, Dinarello CA, Pasagian A: Cachectin/TNF and IL-1 induced by glucose-modified proteins: Role in normal tissue remodelling. Science 240: 1546–1548, 1988[Abstract/Free Full Text]
  100. Miyata T, Oda O, Inagi R, Iida Y, Araki N, Yamada N, Horiuchi S, Taniguchi N, Maeda K, Kinoshita T: ß2-Microglobulin modified with advanced glycation end products is a major component of hemodialysis-associated amyloidosis. J Clin Invest 92: 1243–1252, 1993
  101. Miyata T, Inagi R, Iida Y, Sato M, Yamada N, Oda O, Maeda K, Seo H: Involvement of ß2-microglobulin modified with advanced glycation end products in the pathogenesis of hemodialysis-associated amyloidosis. Induction of human monocyte chemotaxis and macrophage secretion of tumor necrosis factor-{alpha} and interleukin-1. J Clin Invest 93: 521–528, 1994
  102. Makita Z, Bucala R, Rayfield EJ, Friedman EA, Kaufman AM, Korbet SM, Barth RH, Winston JA, Fuh H, Manogue KR, Cerami A, Vlassara H: Reactive glycosylation endproducts in diabetic uraemia and treatment of renal failure. Lancet 343: 1519–1522, 1994[CrossRef][Medline]
  103. Sell DR, Monnier VM: Structure elucidation of a senescence cross-link from human extracellular matrix. J Biol Chem 264: 21597–21602, 1989[Abstract/Free Full Text]
  104. Ahmed MU, Thorpe SR, Baynes JW: Identification of N{Sigma}-carboxymethyllysine as a degradation product of fructoselysine in glycated protein. J Biol Chem 261: 4889–4894, 1986[Abstract/Free Full Text]
  105. Miyata T, Ueda Y, Shinzato T, Iida Y, Tanaka S, Kurokawa K, van Yperselede Strihou C, Maeda K: Accumulation of albumin-linked and free-form pentosidine in the circulation of uremic patients with end-stage renal failure: Renal implications in the pathophysiology of pentosidine. J Am Soc Nephrol 7: 1198–1206, 1996[Abstract]
  106. Miyata T, Fu MX, Kurokawa K, van Yperselede Strihou C, Thorpe SR, Baynes JW: Autoxidation products of both carbohydrates and lipids are increased in uremic plasma: Is there oxidative stress in uremia? Kidney Int 54: 1290–1295, 1998[CrossRef][Medline]
  107. Miyata T, van Ypersele de Strihou C, Kurokawa K, Baynes JW: Alterations in non-enzymatic biochemistry in uremia: Origin and significance of "carbonyl stress" in long-term uremic complications. Kidney Int 55: 389–399, 1999[CrossRef][Medline]
  108. Miyata T, Sugiyama S, Saito A, Kurokawa K: Reactive carbonyl compounds related uremic toxicity ("carbonyl stress"). Kidney Int 59 (suppl 78): S25–S31, 2001
  109. Sugiyama S, Miyata T, Ueda Y, Tanaka H, Maeda K, Kawashima S, van Yperselede Strihou C, Kurokawa K: Plasma level of pentosidine, an advanced glycation end product, in diabetic patients. J Am Soc Nephrol 9: 1681–1688, 1998[Abstract]
  110. Jadoul M, Ueda Y, Yasuda Y, Saito A, Robert A, Ishida N, Kurokawa K, van Ypersele de Strihou C, Miyata T: Influence of hemodialysis membrane type on pentosidine plasma level, a marker of "carbonyl stress.rdquo; Kidney Int 55: 2487–2492, 1999[CrossRef][Medline]
  111. Himmelfarb J, Hakim RM: Biocompatibility and risk of infection in haemodialysis patients. Nephrol Dial Transplant 9 [Suppl 2]: 138–144, 1994[Abstract/Free Full Text]
  112. Witko-Sarsat V, Descamps-Latscha B: Advanced oxidation protein products: Novel uraemic toxins and pro-inflammatory mediators in chronic renal failure? Nephrol Dial Transplant 12: 1310–1312, 1997[Free Full Text]
  113. Witko-Sarsat V, Friedlander M, Khoa TN, Capeillère-Blandin C, Nguyen AT, Canteloup S, Dayer J-M, Jungers P, Drüeke T, Descamps-Latscha B: Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure. J Immunol 161: 2524–2532, 1998[Abstract/Free Full Text]
  114. Himmelfarb J, McMonagle E, McMenamin E: Plasma protein thiol oxidation and carbonyl formation in chronic renal failure. Kidney Int 58: 2571–2578, 2000[CrossRef][Medline]
  115. Daugherty A, Dunn JL, Rateri DL, Heinecke JW: Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions. J Clin Invest 94: 437–444, 1994
  116. Anderson MM, Hazen SL, Hsu FF, Heinecke JW: Human neutrophils employ the myeloperoxidase-hydrogen peroxidechloride system to convert hydroxy-amino acids into glycoaldehyde, 2-hydroxypropanal, and acrolein. A mechanism for the generation of highly reactive alpha-hydroxy and alpha, beta-unsaturated aldehydes by phagocytes at sites of inflammation. J Clin Invest 99: 424–432, 1997[Medline]
  117. Witko-Sarsat V, Nguyen-Khoa T, Jungers P, Drüeke TB, Descamps-Latscha B: Advanced oxidation protein products as a novel molecular basis of oxidative stress in uraemia. Nephrol Dial Transplant 14 [Suppl 1]: 76–78, 1999[Abstract/Free Full Text]
  118. Vanholder R, De Smet R, Waterloos MA, Van Landschoot N, Vogeleere P, Hoste E, Ringoir S: Mechanisms of uremic inhibition of phagocyte reactive species production: Characterization of the role of p-cresol. Kidney Int 47: 510–517, 1995[Medline]
  119. Hirayama A, Noronha-Dutra AA, Gordge MP, Neild GH, Hothersall JS: Inhibition of neutrophil superoxide production by uremic concentrations of guanidino compounds. J Am Soc Nephrol 11: 684–689, 2000[Abstract/Free Full Text]
  120. Hörl WH, Haag-Weber M, Georgopoulos A, Block LH: Physicochemical characterization of a polypeptide present in uremic serum that inhibits the biological activity of polymorphonuclear cells. Proc Natl Acad Sci USA 87: 6353–6357, 1990[Abstract/Free Full Text]
  121. Haag-Weber M, Mai B, Hörl WH: Isolation of a granulocyte inhibitory protein from uraemic patients with homology of beta2-microglobulin. Nephrol Dial Transplant 9: 382–388, 1994[Abstract/Free Full Text]
  122. Cohen G, Haag-Weber M, Mai B, Deicher R, Hörl WH: Effect of immunoglobulin light chains from hemodialysis and CAPD patients on PMNL functions. J Am Soc Nephrol 6: 1592–1599, 1995[Abstract]
  123. Cohen G, Rudnicki M, Hörl WH: Isolation of modified ubiquitin as a neutrophil chemotaxis inhibitor from uremic patients. J Am Soc Nephrol 9: 451–456, 1998[Abstract]
  124. Kokot F, Adamczak M, Wiecek A: Plasma leptin concentration in kidney transplant patients during the early post-transplant period. Nephrol Dial Transplant 13: 2276–2280, 1998[Abstract/Free Full Text]
  125. Fouque D, Juillard L, Lasne Y, Fouque D, Juillard L, Lasne Y, Tabakian A, Laville M, Joly MO, Laville M: Acute leptin regulation in end-stage renal failure: The role of growth hormone and IGF-1. Kidney Int 54: 932–937, 1998[CrossRef][Medline]
  126. Garibotto G, Russo R, Franceschini R, Garibotto G, Russo R, Franceschini R, Robaudo C, Saffioti S, Rolandi E, Deferrari G, Barreca T: Inter-organ leptin exchange in humans. Biochem Biophys Res Commun 247: 504–509, 1998[CrossRef][Medline]
  127. Nordfors L, Lönnqvist F, Heimbürger O, Danielsson A, Schalling M, Stenvinkel P: Low leptin gene expression and hyperleptinaemia in chronic renal failure. Kidney Int 54: 1267–1275, 1998[CrossRef][Medline]
  128. Stenvinkel P, Lönnquist F, Schalling M: Molecular studies of leptin: Implications for renal disease. Nephrol Dial Transplant 14: 1103–1112, 1999[Abstract/Free Full Text]
  129. Stenvinkel P: Leptin and blood pressure—Is there a link? Nephrol Dial Transplant 15: 1115–1117, 2000[Free Full Text]



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Apoptosis of human polymorphonuclear neutrophils accelerated by dialysis membranes via the activation of the complement system
Nephrol. Dial. Transplant., December 1, 2004; 19(12): 3104 - 3111.
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E. J. Mullin, M. S. Metcalfe, and G. J. Maddern
Artificial Liver Support: Potential to Retard Regeneration?
Arch Surg, June 1, 2004; 139(6): 670 - 677.
[Abstract] [Full Text] [PDF]

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