- Email: [email protected]
Interleukin-6 may mediate malnutrition in chronic hemodialysis patients
Interleukin-6 May Mediate Malnutrition in Chronic Hemodialysis Patients Yukiko Kaizu, MS, Masato Kimura, MD, Takashi Yoneyama, MD, Kunihiko Miyaji, MD, Ikuo Hibi, MD, and Hiromichi Kumagai, MD ● Studies were performed to investigate the relationship between serum interleukin-6 (IL-6) and the nutritional status in chronic hemodialysis patients. Serum IL-6 in 45 patients (21 men and 24 women), each with chronic renal failure and having undergone hemodialysis for more than 3 years, was measured before and after a dialysis session. The nutritional status of each patient was evaluated by measuring body mass index (BMI), body weight loss for 3 years, midarm muscle area (MAMA), serum albumin, prealbumin, and insulin-like growth factor-1. Serum IL-6 was significantly higher in the patients undergoing hemodialysis (11.7 ⴞ 2.8 pg/mL) than in healthy volunteers (F0.6 pg/mL). There was no further increase in serum IL-6 after a dialysis session when the extracellular water volume was corrected by the ultrafiltrate volume. Predialytic serum IL-6 was significantly correlated with serum albumin (r ⴝ ⴚ0.4, P ⴝ 0.006), cholinesterase (r ⴝ ⴚ0.51, P ⴝ 0.001), body weight change for 3 years (r ⴝ ⴚ0.48, P ⴝ 0.001) and MAMA r ⴝ ⴚ0.39, P ⴝ 0.05). With the patients divided into two groups, a high serum IL-6 (G10 pg/mL) group and low serum IL-6 (F10 pg/mL) group, the body weight loss for 3 years (ⴚ4.60% ⴞ 1.39% v 0.76 ⴞ 0.75%, P F 0.01) was significantly higher, and the serum albumin level (3.66 ⴞ 0.10 g/dL v 3.96 ⴞ 0.05 g/dL, P F 0.05) was significantly lower in those patients with high serum IL-6 than in those with low serum IL-6. The results of a multiple regression analysis indicated that the serum IL-6 level was dependent on the duration of hemodialysis, age, and the dialysis membrane properties. These results suggest that the nutritional status in chronic hemodialysis patients was affected, at least in part, by the circulating IL-6 level. Multiple factors, such as long-term hemodialysis, aging, and the use of a regenerated cellulose membrane dialyzer, were associated with this increased level of IL-6. r 1998 by the National Kidney Foundation, Inc. INDEX WORDS: Interleukin-6; malnutrition; hemodialysis; weight loss; biocompatibility.
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ALNUTRITION is associated with mortality and morbidity in chronic hemodialysis patients.1-4 The increase in catabolism is an important factor of malnutrition5,6 in hemodialyzed patients, and it might be ascribed to or accelerated by acidosis,7,8 intradialytic factors, or complications from chronic inflammatory disorders.9 Intradialytic factors include amino acid and albumin loss in the dialysate10,11 and inadequate biocompatibility of the dialysis membrane.12-14 Biocompatibility of the dialysis membrane is defined as the degree of such unfavorable reactions as a release of complements and stimulation of the coagulation process, which is induced by contact between the blood and dialysis membrane. Increased catabolism by a bioincompatible membrane might be mediated by an inflammatory process.9 Another factor inducing malnutrition in chronic hemodialysis patients is decreased protein synthesis. Kaysen et al15 have measured the kinetics of [125I] human albumin in hemodialysis patients and found that hypoalbuminemia was caused by decreased albumin synthesis. The factor affecting albumin synthesis was suggested to be nondietary and partially related to the acutephase response.
Cytokines have been recognized as inflammatory mediators in a variety of organs. The acute-phase response in the inflammatory process involves the increased synthesis of such acute-phase reactants as C-reactive protein (CRP) and sialic acid and the suppression of albumin and transferrin synthesis. Among various kinds of cytokines, interleukin-6 (IL-6) serves as an important multifunctional cytokine for regulating immune functions and hematopoiesis.16 IL-6 also induces the synthesis of major acute-phase proteins and inhibits the production of albumin, whereas Interleukin-1 (IL-1) or the tumor necroFrom the Department of Clinical Nutrition, School of Food and Nutritional Sciences, University of Shizuoka, School of Nursing, University of Shizuoka, and Miyaji Hospital, Japan. Received January 2, 1997; accepted in revised form July 11, 1997. Supported in part by a research grant from Shizuoka Research and Education Foundation. Address reprint requests to Hiromichi Kumagai, MD, Associate Professor, Department of Clinical Nutrition, School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Shizuoka, 422, Japan. E-mail: [email protected]
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3101-0016$3.00/0
American Journal of Kidney Diseases, Vol 31, No 1 (January), 1998: pp 93-100
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sis factor (TNF) stimulates the generation of only a limited subset of the acute-phase proteins. Furthermore, IL-6 stimulates the breakdown of muscle protein17,18 and has been postulated to be a promoter of cancer cachexia.19 In hemodialyzed patients, the serum level of IL-6 has been reported to be higher than that in continuous ambulatory peritoneal dialysis (CAPD) patients or in a normal control.20-22 This increase in IL-6 is probably attributable to the stimulation in production by certain dialysis procedures, because CAPD patients showed no such high level of IL-6. All of this evidence suggests that IL-6 might be related to malnutrition in patients undergoing hemodialysis by two different mechanisms: decreased albumin synthesis and accelerated protein catabolism. In this study, we examined the relationship between the nutritional parameters and circulating IL-6 level and the factors affecting serum IL-6 level in patients with chronic renal failure undergoing hemodialysis. METHODS
Patients Forty-five patients (21 men and 24 women) with chronic renal failure who had been undergoing hemodialysis for more than 3 years were assigned to this study. The mean age was 59.1 ⫾ 1.9 years (range, 23 to 80). Their primary renal diseases were chronic glomerulonephritis in 43 patients, polycystic kidney in one, and nephrosclerosis in another. All patients were being subjected to the regular hemodialysis prescription with hollow-fiber dialyzers at a dialysate flow rate of 500 mL/min and a blood flow rate of 200 mL/min for 4 hours three times per week. Dialyzers made from low-flux ultrafiltration rate (UFR) ⬍10 mL/hr·mm Hg) regenerated cellulose hollow-fiber (cuprammonium rayon; Asahi Medical, Tokyo, Japan) were used in 13 patients, modified cellulose hollow-fiber in 13 patients, and synthetic hollowfiber in 19 patients. The modified cellulose hollow-fiber included low-flux Hemophane (Nikkiso, Tokyo, Japan; n ⫽ 6) and medium-flux (UFR 10-40 mL/hr·mm Hg) cellulose triacetate (CTA; Nipro, Osaka, Japan; n ⫽ 7), but the synthetic hollow fiber included high-flux (UFR ⬎ 40 mL/ hr·mm Hg) polysulfone (PS; Fresenius, Tokyo, Japan; n ⫽ 9), medium-flux polymethylmethacrylate (PMMA; Toray, Tokyo, Japan; n ⫽ 1), and medium-flux polyethersulfone/polyarylate polymer alloy (PEPA; Nikkiso, Tokyo, Japan; n ⫽ 9). These dialyzers were sterilized by gamma ray or high-pressure steam and were disposed of after a single use. A bicarbonate dialysate (Kindaly AF-2P; Fuso, Osaka, Japan) containing sodium (140 mEq/L), potassium (2 mEq/ L), calcium (3 mEq/L), magnesium (1 mEq/L), chloride (110 mEq/L), bicarbonate (30 mEq/L), acetate (8 mEq/L), and glucose (100 mg/dL) was used for all the treatments during this study. Tap water was filtered to remove bacteria
and pyrogen by an ultrafiltration unit with reverse osmosis, and then used to dilute the concentrated dialysate. The diluted dialysate was delivered to the patients without any other sterilization. No patient showed any sign of infection at the time of the study. Blood samples were drawn from the arterial site of the arteriovenous fistula at the start and at the end of dialysis session. The serum was separated and stored at ⫺30°C until needed for analysis. Body weight was measured before and after each dialysis, the postdialytic body weight being used as the dry weight. Body weight change for 3 years was calculated as the difference in dry weight between 1996 and 1993. The MAMA was calculated from the mid-arm circumference, this being measured at the midpoint between the acromial process and the olecranon process, and the triceps skinfold thickness.
Analytic Procedures Serum urea nitrogen, creatinine, albumin, total cholesterol, triglyceride, and cholinesterase were measured by standard laboratory techniques with an automatic analyzer. Prealbumin and C-reactive protein were measured by laser nepherometry, and sialic acid was determined by an enzymatic assay. Determinations of IL-6 (Ultrasensitive human IL-6 immunoassay kit; Biosource International, Camarillo, CA) and insulin-like growth factor 1 (IGF-1; Somatomedin-C II, Ciba-Corning, Tokyo, Japan) were performed by an enzyme-linked immunoassay and radioimmunoassay, respectively. A single-pool urea kinetic model was used to calculate the protein catabolic rate (PCR) and the delivered dose of dialysis (Kt/Vurea) as previously described.23 The postdialytic concentration of IL-6 was corrected for ultrafiltration by the formula of Bergstro¨m and Wehle.24
Statistical Analysis Data are expressed as mean ⫾ SEM, differences between groups being analyzed by a one-way analysis of variance and then the Newman-Keuls test. Single- or multipleregression analyses were applied to examine the relationship between IL-6 and various parameters. P values less than 0.05 are considered statistically significant, although P values less than 0.1 are also presented. All statistical calculations were performed with GB-STAT software (Dynamic Microsystems, Silver Spring, MD).
RESULTS
Serum IL-6 values in all healthy volunteers were under the detection limit for the highsensitivity IL-6 RIA kit (⬍0.6 pg/mL). Serum IL-6 was significantly higher in the patients undergoing hemodialysis than in the healthy volunteers, and it increased slightly after a dialysis session had been conducted (Fig 1B). However, postdialytic IL-6 was slightly lower than predialytic IL-6 when the extracellular water volume was corrected for the ultrafiltrate volume (Fig 1C). There was no statistical differ-
IL-6 AND MALNUTRITION IN HEMODIALYSIS
Fig 1. Serum IL-6 concentrations in five healthy volunteers (A) and in chronic hemodialysis patients at the start (pre) and end (post) of a single dialysis session (B, uncorrected for the ultrafiltrate volume; C, corrected for the ultrafiltrate volume).
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showed no correlation with serum albumin (r ⫽ 0.14, NS), prealbumin (r ⫽ 0.31, NS), IGF-1 (r ⫽ 0.01, NS), and body weight loss for 3 years (r ⫽ 0.11, NS). The adequacy of dialysis evaluated by Kt/V also had no correlation with any nutritional parameters measured in this study. There was no difference in either Kt/Vurea or PCR between high–IL-6 patients (Kt/Vurea, 1.52 ⫾ 0.06; PCR, 1.34 ⫾ 0.08 g/kg/day) and low–IL-6 patients (Kt/Vurea, 1.46 ⫾ 0.06; PCR, 1.23 ⫾ 0.08 g/kg/day). In an effort to explore the effect of the dialysis membrane on the serum IL-6 level, predialytic IL-6 was compared between the patients dialyzed with a low-flux regenerated cellulose membrane dialyzer, those dialyzed with a low- or medium-flux modified cellulose and synthetic Table 1. Correlation Between Predialytic Serum IL-6 and Nutritional Parameters
ence between predialysis and postdialysis IL-6 even in the patients dialyzed with high-flux membrane. Single correlation coefficients between predialytic IL-6 and various parameters exhibiting nutritional status are shown in Table 1. The body weight change for the last 3 years, midarm muscle area, serum albumin, and cholinesterase had a significantly negative correlation with predialytic IL-6. The duration of hemodialysis and sialic acid, one of the acute-phase reactants, were significantly correlated with predialytic IL-6. Age and another acute-phase reactant, CRP, tended to correlate with predialytic IL-6, although the value was statistically insignificant. Comparisons of the major nutritional parameters are made between the patients with IL-6 values of more than 10 pg/mL, the approximate median value, and those with IL-6 values of less than 10 pg/mL in Fig 2. The patients with high IL-6 had lost body weight by more than 4% (⫺1.9 ⫾ 0.7 kg), whereas the patients with low IL-6 had slightly gained body weight. MAMA, serum albumin, and serum creatinine were also significantly lower in the high–IL-6 patients than in the low–IL-6 patients. BMI, prealbumin, and IGF-1 tended to be higher in the high–IL-6 patients than in the low–IL-6 patients. PCR, which was measured to determine whether food intake affected nutritional status,
Clinical Variable
Correlation Coefficient
P Value
Age Duration of HD Body mass index Body weight change for 3 years Mid-arm muscle area Systolic blood pressure Diastolic blood pressure Cardiothoracic ratio Interdialytic increase in body weight Hematocrit Total protein Serum albumin Prealbumin IGF-1 Cholinesterase Total cholesterol Triglyceride BUN Serum creatinine 2-microglobulin Serum K Serum Ca Serum phosphate Serum chloride Kt/Vurea PCR C-reactive protein Sialic acid
0.27 0.32 ⫺0.22 ⫺0.48 ⫺0.39 ⫺0.27 ⫺0.34 0.32 0.04 ⫺0.22 0.13 ⫺0.40 ⫺0.29 0.01 ⫺0.51 ⫺0.19 ⫺0.20 0.27 ⫺0.31 0.01 0.01 ⫺0.11 0.11 ⫺0.15 0.29 0.10 0.28 0.45
0.07 0.03 * 0.001 0.05 0.07 0.02 0.03 * * * 0.006 0.06 * 0.01 * * 0.08 0.04 * * * * * * * 0.06 0.008
Abbreviations: HD, hemodialysis; IGF-1, insulin-like growth factor-1; BUN, blood urea nitrogen; Kt/Vurea, amount of dialysis delivered to a patient per treatment; PCR, protein catabolic rate. *P ⬎ 0.1.
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Fig 3. Effect of dialysis membrane characteristics on serum IL-6. *P F .05 vs low-flux regenerated cellulose.
(v the synthetic membrane) were associated significantly with the serum IL-6 level, whereas the effect of the high-flux dialyzer (v the mediumand low-flux dialyzers) failed to show any relationship with the IL-6 elevation. DISCUSSION Fig 2. Differences in the nutritional parameters between patients with an IL-6 level of more than 10 pg/mL (n ⴝ 34) and those with IL-6 of more than 10 pg/mL (n ⴝ 11). *P F 0.05; **P F 0.01. Abbreviations: BMI, body mass index; BW, body weight; MAMA, midarm muscle area; IGF-1, insulin-like growth factor-1.
membrane dialyzer, and those dialyzed with a high-flux synthetic membrane dialyzer (Fig 3). IL-6 was significantly higher in the low-flux regenerated cellulose membrane group than in the low- or medium-flux modified cellulose and synthetic membrane group. It also tended to be higher in the high-flux synthetic membrane group than in the low- or medium-flux modified cellulose and synthetic membrane group, although the difference was not statistically significant. Because the predialytic serum IL-6 level seemed to be influenced by the duration of hemodialysis, age, and the dialysis membrane characteristics, a multiple-regression analysis was applied to obviate the factors affecting the serum IL-6 level (Table 2). Age, the duration of hemodialysis, and the regenerated cellulose membrane
Our study has shown that the serum IL-6 level was significantly correlated with major parameters indicating malnutrition, such as body weight loss and serum albumin level. When the nutritional parameters were compared between those patients with high IL-6 (⬎10 pg/mL) and those with low IL-6 (⬍10 pg/mL), the association of IL-6 with nutrition was more pronounced. The body weight loss, which is a dynamic parameter of nutrition and is recognized as a predictor of mortality in many studies,25-27 was more than 4% Table 2. Multiple-Regression Analyses of the Effect of Age, the Duration of Hemodialysis, Characteristics of the Dialysis Membrane, and the Flux of the Dialysis Membrane Upon Subjecting 45 Chronic Dialysis Patients to Predialytic Serum IL-6 Independent Variable
Coefficient
SE
Duration of dialysis Regenerated cellulose Age High flux
0.080 0.887 0.030 0.444
0.025 0.321 0.011 0.366
t-value P Value
3.21 2.75 2.69 1.21
0.0026 0.0087 0.0103 0.2328
NOTE. Multiple r ⫽ 0.607, F ⫽ 5.82, P ⫽ 0.0009. Abbreviations: coefficient, partial regression coefficient; SE, standard error.
IL-6 AND MALNUTRITION IN HEMODIALYSIS
over the preceding 3 years in those patients with high IL-6, whereas the patients with low IL-6 did not lose weight. In those patients with high IL-6, MAMA and serum creatinine were significantly lower than those in the patients with low IL-6, suggesting that IL-6 mediated muscle loss. In addition, the patients with high IL-6 had significantly lower serum albumin and cholinesterase levels than the patients with low IL-6. Because body weight change and serum albumin are late indices of malnutrition, we measured the more rapid and sensitive indicators of protein nutrition, prealbumin and IGF-1. Prealbumin and IGF-1 also tended to be lower in the patients with high IL-6 than in those with low IL-6. This collective evidence suggests that serum IL-6 level was associated with the nutritional disturbance in the chronic hemodialysis patients. IL-6 mediates the acute-phase response, which was characterized by an increased synthesis of acute-phase reactants including CRP, fibrinogen, and amyloid A protein, and by a reduced synthesis of albumin and transferrin by hepatocytes.16 IL-6 is considered to act synergistically with TNF-␣ and IL-1 to downregulate albumin mRNA and thus inhibit albumin synthesis.28 In fact, serum IL-6 was positively correlated with CRP and sialic acid and showed inverse correlation with serum albumin in our study. Kaysen et al15 have shown that the rate of albumin synthesis was negatively correlated with ␣2-macroglobulin, a carrier protein of IL-6, and that the serum albumin concentration was inversely correlated with acute-phase proteins, ␣2-macroglobulin, CRP, and ferritin by a multiple-regression analysis. These findings support IL-6 being associated with suppressed albumin synthesis in chronic hemodialysis patients. Furthermore, IL-6 has been known to stimulate muscle proteolysis in many chronic neoplastic or inflammatory diseases.17,18 Although other cytokines such as IL-1 and TNF have been reported to be involved in muscle protein catabolism, IL-6 appeared to have a more significant role than TNF in mediating cancer cachexia.19 The evidence that MAMA and serum creatinine in the high–IL-6 patients was lower than that in the low–IL-6 patients in our study supports the effect of IL-6 on muscle protein catabolism in chronic dialysis patients.
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Cytokines have also been reported to suppress appetite, by which malnutrition might be accelerated.29 With our cases, however, there was no difference in PCR, an indicator of dietary protein intake under stable conditions, between the patients with a high IL-6 and those with a low IL-6 level. The serum IL-6 level measured by either a bioassay20,21 or enzyme-linked immunosorbent assay (ELISA22) has been reported to increase in patients with chronic renal failure. Hemodialyzed patients in particular have shown a higher level of IL-6 than CAPD patients or uremic patients without dialysis, suggesting that hemodialysis stimulated IL-6 production.22 The reports comparing IL-6 between prehemodialysis and posthemodialysis indicated that serum IL-6 did not increase during a hemodialysis session if the postdialysis IL-6 value was corrected by the ultrafiltrate volume.20 However, the plasma IL-6 level had significantly increased within a few hours after the end of the dialysis session, a time consistent with the activation of monocytes.20 An increased expression of IL-6 mRNA in peripheral blood mononuclear cells (PBMC) was found in patients undergoing hemodialysis in comparison with healthy controls, and a further increase was detected during a hemodialysis session.30 This collective evidence suggests that the high IL-6 level in hemodialyzed patients was attributable to the stimulation of monocytes by the hemodialysis. Proposed mechanisms for stimulating monocytes and releasing IL-6 production during hemodialysis include blood interaction with the hemodialysis membrane and backleakage of endotoxin from the contaminated dialysate through a high-flux dialysis membrane.31 Another possibility for the increase of serum IL-6 level in chronic dialysis patients is due to superimposed illnesses. One of the important illnesses that complicate hemodialysis is dialysisrelated amyloidosis. Miyata et al32 have recently reported that advanced glycosylation productmodified 2-microglobulin, which has been recognized as the major precursor protein of dialysisrelated amyloidosis, enhanced chemotaxis and chemokinesis of human monocytes and enhanced the secretion of cytokines. This fact suggests the possibility that patients with dialysisrelated amyloidosis would have a high serum
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IL-6 level. In fact, it has been reported that long-term hemodialysis patients complicated with dialysis-related amyloidosis attained a high serum IL-6 level.33 However, it cannot be discounted that other chronic illnesses that induce an inflammatory response might also influence the serum IL-6 level. The incidence of dialysis-related amyloidosis is related to the duration of hemodialysis and age. A close relationship has been found between the duration of dialysis and the prevalence of amyloid deposition in the synovial and juxtaarticular bone.34 The symptoms of dialysisrelated amyloidosis seem to occur sooner after the start of hemodialysis as age advances.35 Based on all of this evidence, we applied a multipleregression analysis to elucidate the contribution of membrane characteristics, membrane flux, duration of hemodialysis, and age on the serum IL-6 level. The results show that serum IL-6 was dependent on the age, duration of hemodialysis, and the use of a regenerated cellulose membrane. The use of a regenerated cellulose membrane was associated with the increase in serum IL-6 level from the results of this study. However, there is still controversy as to whether the biocompatibility of the dialysis membrane is related to IL-6 production. PBMC of uremic patients who had been regularly hemodialyzed with a cuprophane dialyzer produced a higher amount of IL-6 than PBMC of patients dialyzed with a PMMA dialyzer.36 A similar result for monocyte IL-6 release was obtained after an in vitro stimulation of whole blood with 10 ng/mL lipopolysaccharides.37 Previous in vivo studies in which a bioassay of IL-6 was conducted, however, have failed to show any difference in the serum IL-6 level between cellulosic membranes and synthetic membranes.20,22 On the contrary, we could detect a difference in serum IL-6 level between those patients dialyzed with a regenerated cellulose membrane and those dialyzed with a modified cellulose or synthetic membrane, apart from a high-flux dialyzer. Both of the previous studies20,22 compared the predialytic IL-6 level between patients treated with cellulosic membranes and polyacrylonitrile (PANAN69) membranes. Although UFR for the two membranes was not stated in the articles, it is possible that the use of a high-flux PAN mem-
KAIZU ET AL
brane might increase IL-6 to the level of the cellulosic membrane users, as shown in our study. It has been reported that the biocompatibility of a dialysis membrane might have an impact on the nutritional status of chronic dialysis patients. Parker et al38 have reported that a biocompatible dialysis membrane has a favorable effect on nutritional status in comparison with a bioincompatible membrane. In their prospective study, patients dialyzed with a biocompatible membrane underwent an increase in dry weight of more than 4 kg over 18 months and a rapid increase in IGF-1 and serum albumin, whereas the patients dialyzed with a bioincompatible membrane showed no change in body weight and serum albumin. More recently, Hakim et al39 have shown that the relative risk of mortality to patients dialyzed with a modified cellulose or synthetic membrane was at least 20% less than that to patients treated with an unsubstituted cellulose membrane. Combining our data with these results, the use of a biocompatible membrane dialyzer might provide great benefits to chronic hemodialysis patients. The results of this study suggest that the serum IL-6 level is one of the relevant factors for nutritional status in chronic dialysis patients. The patients with a high serum IL-6 level had lost body weight over the preceding 3 years and had lower serum albumin and cholinesterase levels than the patients with a low serum IL-6 level. The duration of dialysis, age, and the use of a regenerated cellulose membrane were related to the serum IL-6 level. ACKNOWLEDGMENT The authors thank A.K.J. Innes and Akihito Morita for helpful advice in preparing the manuscript.
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interleukin-6 in long-term hemodialyzed patients. Nephron 60:307-313, 1992 23. Daugirdas JT: Second generation logarithmic estimates of single pool variable volume of Kt/V: An analysis of error. J Am Soc Nephrol 4:1205-1213, 1993 24. Bergstro¨m J, Wehle B: No change in corrected 2-microglobulin concentration after cuprophan hemodialysis. Lancet 1:628-629, 1987 25. Lee IM, Paffenbarger RS: Change in body weight and longevity. JAMA 268:2045-2049, 1992 26. Pamuk ER, Williamson DF, Serdula MK, Madans J, Byers TE: Weight loss and subsequent death in a cohort of US adults. Ann Intern Med 119:744-748, 1993 27. Andres R, Muller DC, Sorkin JD: Long-term effects of change in body weight on all-cause mortality: A review. Ann Intern Med 119:737-743, 1993 28. Andus T, Geiger T, Hirano T, Kishimoto T, Heinrich PC: Action of recombinant human interleukin 6, interleukin 1 and tumor necrosis factor ␣ on the mRNA induction of acute-phase proteins. Eur J Immunol 18:739-746, 1988 29. Moldawer LL, Andersson C, Gelin J, Lundholm KG: Regulation of food intake and hepatic protein synthesis by recombinant-derived cytokines. Am J Physiol 254:G450G456, 1988 30. Pertosa G, Gesualdo L, Tarantino EA, Ranieri E, Bottalico D, Schena FP: Influence of hemodialysis on interleukin-6 production and gene expression by peripheral blood mononuclear cells. Kidney Int 43:S149-S153, 1993 (suppl) 31. Sundaram S, Barrett TW, Meyer KB, Perrella C, Neto MC, King AJ, Pereira JG: Transmembrane passage of cytokine-inducing bacterial products across new and reprocessed polysulfone dialyzers. J Am Soc Nephrol 7:21832191, 1996 32. Miyata T, Inagi R, Iida Y, Sato M, Yamada N, Oda O, Maeda K, Seo H: Involvement of beta 2-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 33. Takasu S, Takatsu S, Kunitomo K, Kokumai Y: Serum hyaluronic acid and interleukin-6 as possible markers of carpal tunnel syndrome in chronic hemodialysis patients. Artif Organs 18:420-424, 1994 34. Bardin T, Kuntz D, Zingraff J, Voisin MC, Zelmar A, Lansaman J: Synovial amyloidosis in patients undergoing long-term hemodialysis. Arthritis Rheum 28:1052-1058, 1985 35. van Ypersele de Strihou C, Jadoul M, Malghem J, Maldague B, Jamart J: Effect of dialysis membrane and patient’s age on signs of dialysis-related amyloidosis. Kidney Int 39:1012-1019, 1991 36. Memoli B, Libetta C, Rampino T, Canton AD, Conte G, Scala G, Ruocco MR, Andreucci VE: Hemodialysis related induction of interleukin-6 production by peripheral mononuclear cells. Kidney Int 42:320-326, 1992 37. Engelberts I, Francot GJM, Leunissen KML, Haenen
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B, Ceska M, van der Linden CJ, Burman WA: Effect of hemodialysis on peripheral blood monocyte tumor necrosis factor-␣, interleukin-6, and interleukin-8 secretion in vitro. Nephron 66:396-403, 1994 38. Parker TF III, Wingard RL, Husni L, Ikizler TA, Parker RA, Hakim RM: Effect of the membrane biocompat-
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ibility on nutritional parameters in chronic hemodialysis patients. Kidney Int 49:551-556, 1996 39. 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
M
ALNUTRITION is associated with mortality and morbidity in chronic hemodialysis patients.1-4 The increase in catabolism is an important factor of malnutrition5,6 in hemodialyzed patients, and it might be ascribed to or accelerated by acidosis,7,8 intradialytic factors, or complications from chronic inflammatory disorders.9 Intradialytic factors include amino acid and albumin loss in the dialysate10,11 and inadequate biocompatibility of the dialysis membrane.12-14 Biocompatibility of the dialysis membrane is defined as the degree of such unfavorable reactions as a release of complements and stimulation of the coagulation process, which is induced by contact between the blood and dialysis membrane. Increased catabolism by a bioincompatible membrane might be mediated by an inflammatory process.9 Another factor inducing malnutrition in chronic hemodialysis patients is decreased protein synthesis. Kaysen et al15 have measured the kinetics of [125I] human albumin in hemodialysis patients and found that hypoalbuminemia was caused by decreased albumin synthesis. The factor affecting albumin synthesis was suggested to be nondietary and partially related to the acutephase response.
Cytokines have been recognized as inflammatory mediators in a variety of organs. The acute-phase response in the inflammatory process involves the increased synthesis of such acute-phase reactants as C-reactive protein (CRP) and sialic acid and the suppression of albumin and transferrin synthesis. Among various kinds of cytokines, interleukin-6 (IL-6) serves as an important multifunctional cytokine for regulating immune functions and hematopoiesis.16 IL-6 also induces the synthesis of major acute-phase proteins and inhibits the production of albumin, whereas Interleukin-1 (IL-1) or the tumor necroFrom the Department of Clinical Nutrition, School of Food and Nutritional Sciences, University of Shizuoka, School of Nursing, University of Shizuoka, and Miyaji Hospital, Japan. Received January 2, 1997; accepted in revised form July 11, 1997. Supported in part by a research grant from Shizuoka Research and Education Foundation. Address reprint requests to Hiromichi Kumagai, MD, Associate Professor, Department of Clinical Nutrition, School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Shizuoka, 422, Japan. E-mail: [email protected]
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3101-0016$3.00/0
American Journal of Kidney Diseases, Vol 31, No 1 (January), 1998: pp 93-100
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sis factor (TNF) stimulates the generation of only a limited subset of the acute-phase proteins. Furthermore, IL-6 stimulates the breakdown of muscle protein17,18 and has been postulated to be a promoter of cancer cachexia.19 In hemodialyzed patients, the serum level of IL-6 has been reported to be higher than that in continuous ambulatory peritoneal dialysis (CAPD) patients or in a normal control.20-22 This increase in IL-6 is probably attributable to the stimulation in production by certain dialysis procedures, because CAPD patients showed no such high level of IL-6. All of this evidence suggests that IL-6 might be related to malnutrition in patients undergoing hemodialysis by two different mechanisms: decreased albumin synthesis and accelerated protein catabolism. In this study, we examined the relationship between the nutritional parameters and circulating IL-6 level and the factors affecting serum IL-6 level in patients with chronic renal failure undergoing hemodialysis. METHODS
Patients Forty-five patients (21 men and 24 women) with chronic renal failure who had been undergoing hemodialysis for more than 3 years were assigned to this study. The mean age was 59.1 ⫾ 1.9 years (range, 23 to 80). Their primary renal diseases were chronic glomerulonephritis in 43 patients, polycystic kidney in one, and nephrosclerosis in another. All patients were being subjected to the regular hemodialysis prescription with hollow-fiber dialyzers at a dialysate flow rate of 500 mL/min and a blood flow rate of 200 mL/min for 4 hours three times per week. Dialyzers made from low-flux ultrafiltration rate (UFR) ⬍10 mL/hr·mm Hg) regenerated cellulose hollow-fiber (cuprammonium rayon; Asahi Medical, Tokyo, Japan) were used in 13 patients, modified cellulose hollow-fiber in 13 patients, and synthetic hollowfiber in 19 patients. The modified cellulose hollow-fiber included low-flux Hemophane (Nikkiso, Tokyo, Japan; n ⫽ 6) and medium-flux (UFR 10-40 mL/hr·mm Hg) cellulose triacetate (CTA; Nipro, Osaka, Japan; n ⫽ 7), but the synthetic hollow fiber included high-flux (UFR ⬎ 40 mL/ hr·mm Hg) polysulfone (PS; Fresenius, Tokyo, Japan; n ⫽ 9), medium-flux polymethylmethacrylate (PMMA; Toray, Tokyo, Japan; n ⫽ 1), and medium-flux polyethersulfone/polyarylate polymer alloy (PEPA; Nikkiso, Tokyo, Japan; n ⫽ 9). These dialyzers were sterilized by gamma ray or high-pressure steam and were disposed of after a single use. A bicarbonate dialysate (Kindaly AF-2P; Fuso, Osaka, Japan) containing sodium (140 mEq/L), potassium (2 mEq/ L), calcium (3 mEq/L), magnesium (1 mEq/L), chloride (110 mEq/L), bicarbonate (30 mEq/L), acetate (8 mEq/L), and glucose (100 mg/dL) was used for all the treatments during this study. Tap water was filtered to remove bacteria
and pyrogen by an ultrafiltration unit with reverse osmosis, and then used to dilute the concentrated dialysate. The diluted dialysate was delivered to the patients without any other sterilization. No patient showed any sign of infection at the time of the study. Blood samples were drawn from the arterial site of the arteriovenous fistula at the start and at the end of dialysis session. The serum was separated and stored at ⫺30°C until needed for analysis. Body weight was measured before and after each dialysis, the postdialytic body weight being used as the dry weight. Body weight change for 3 years was calculated as the difference in dry weight between 1996 and 1993. The MAMA was calculated from the mid-arm circumference, this being measured at the midpoint between the acromial process and the olecranon process, and the triceps skinfold thickness.
Analytic Procedures Serum urea nitrogen, creatinine, albumin, total cholesterol, triglyceride, and cholinesterase were measured by standard laboratory techniques with an automatic analyzer. Prealbumin and C-reactive protein were measured by laser nepherometry, and sialic acid was determined by an enzymatic assay. Determinations of IL-6 (Ultrasensitive human IL-6 immunoassay kit; Biosource International, Camarillo, CA) and insulin-like growth factor 1 (IGF-1; Somatomedin-C II, Ciba-Corning, Tokyo, Japan) were performed by an enzyme-linked immunoassay and radioimmunoassay, respectively. A single-pool urea kinetic model was used to calculate the protein catabolic rate (PCR) and the delivered dose of dialysis (Kt/Vurea) as previously described.23 The postdialytic concentration of IL-6 was corrected for ultrafiltration by the formula of Bergstro¨m and Wehle.24
Statistical Analysis Data are expressed as mean ⫾ SEM, differences between groups being analyzed by a one-way analysis of variance and then the Newman-Keuls test. Single- or multipleregression analyses were applied to examine the relationship between IL-6 and various parameters. P values less than 0.05 are considered statistically significant, although P values less than 0.1 are also presented. All statistical calculations were performed with GB-STAT software (Dynamic Microsystems, Silver Spring, MD).
RESULTS
Serum IL-6 values in all healthy volunteers were under the detection limit for the highsensitivity IL-6 RIA kit (⬍0.6 pg/mL). Serum IL-6 was significantly higher in the patients undergoing hemodialysis than in the healthy volunteers, and it increased slightly after a dialysis session had been conducted (Fig 1B). However, postdialytic IL-6 was slightly lower than predialytic IL-6 when the extracellular water volume was corrected for the ultrafiltrate volume (Fig 1C). There was no statistical differ-
IL-6 AND MALNUTRITION IN HEMODIALYSIS
Fig 1. Serum IL-6 concentrations in five healthy volunteers (A) and in chronic hemodialysis patients at the start (pre) and end (post) of a single dialysis session (B, uncorrected for the ultrafiltrate volume; C, corrected for the ultrafiltrate volume).
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showed no correlation with serum albumin (r ⫽ 0.14, NS), prealbumin (r ⫽ 0.31, NS), IGF-1 (r ⫽ 0.01, NS), and body weight loss for 3 years (r ⫽ 0.11, NS). The adequacy of dialysis evaluated by Kt/V also had no correlation with any nutritional parameters measured in this study. There was no difference in either Kt/Vurea or PCR between high–IL-6 patients (Kt/Vurea, 1.52 ⫾ 0.06; PCR, 1.34 ⫾ 0.08 g/kg/day) and low–IL-6 patients (Kt/Vurea, 1.46 ⫾ 0.06; PCR, 1.23 ⫾ 0.08 g/kg/day). In an effort to explore the effect of the dialysis membrane on the serum IL-6 level, predialytic IL-6 was compared between the patients dialyzed with a low-flux regenerated cellulose membrane dialyzer, those dialyzed with a low- or medium-flux modified cellulose and synthetic Table 1. Correlation Between Predialytic Serum IL-6 and Nutritional Parameters
ence between predialysis and postdialysis IL-6 even in the patients dialyzed with high-flux membrane. Single correlation coefficients between predialytic IL-6 and various parameters exhibiting nutritional status are shown in Table 1. The body weight change for the last 3 years, midarm muscle area, serum albumin, and cholinesterase had a significantly negative correlation with predialytic IL-6. The duration of hemodialysis and sialic acid, one of the acute-phase reactants, were significantly correlated with predialytic IL-6. Age and another acute-phase reactant, CRP, tended to correlate with predialytic IL-6, although the value was statistically insignificant. Comparisons of the major nutritional parameters are made between the patients with IL-6 values of more than 10 pg/mL, the approximate median value, and those with IL-6 values of less than 10 pg/mL in Fig 2. The patients with high IL-6 had lost body weight by more than 4% (⫺1.9 ⫾ 0.7 kg), whereas the patients with low IL-6 had slightly gained body weight. MAMA, serum albumin, and serum creatinine were also significantly lower in the high–IL-6 patients than in the low–IL-6 patients. BMI, prealbumin, and IGF-1 tended to be higher in the high–IL-6 patients than in the low–IL-6 patients. PCR, which was measured to determine whether food intake affected nutritional status,
Clinical Variable
Correlation Coefficient
P Value
Age Duration of HD Body mass index Body weight change for 3 years Mid-arm muscle area Systolic blood pressure Diastolic blood pressure Cardiothoracic ratio Interdialytic increase in body weight Hematocrit Total protein Serum albumin Prealbumin IGF-1 Cholinesterase Total cholesterol Triglyceride BUN Serum creatinine 2-microglobulin Serum K Serum Ca Serum phosphate Serum chloride Kt/Vurea PCR C-reactive protein Sialic acid
0.27 0.32 ⫺0.22 ⫺0.48 ⫺0.39 ⫺0.27 ⫺0.34 0.32 0.04 ⫺0.22 0.13 ⫺0.40 ⫺0.29 0.01 ⫺0.51 ⫺0.19 ⫺0.20 0.27 ⫺0.31 0.01 0.01 ⫺0.11 0.11 ⫺0.15 0.29 0.10 0.28 0.45
0.07 0.03 * 0.001 0.05 0.07 0.02 0.03 * * * 0.006 0.06 * 0.01 * * 0.08 0.04 * * * * * * * 0.06 0.008
Abbreviations: HD, hemodialysis; IGF-1, insulin-like growth factor-1; BUN, blood urea nitrogen; Kt/Vurea, amount of dialysis delivered to a patient per treatment; PCR, protein catabolic rate. *P ⬎ 0.1.
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Fig 3. Effect of dialysis membrane characteristics on serum IL-6. *P F .05 vs low-flux regenerated cellulose.
(v the synthetic membrane) were associated significantly with the serum IL-6 level, whereas the effect of the high-flux dialyzer (v the mediumand low-flux dialyzers) failed to show any relationship with the IL-6 elevation. DISCUSSION Fig 2. Differences in the nutritional parameters between patients with an IL-6 level of more than 10 pg/mL (n ⴝ 34) and those with IL-6 of more than 10 pg/mL (n ⴝ 11). *P F 0.05; **P F 0.01. Abbreviations: BMI, body mass index; BW, body weight; MAMA, midarm muscle area; IGF-1, insulin-like growth factor-1.
membrane dialyzer, and those dialyzed with a high-flux synthetic membrane dialyzer (Fig 3). IL-6 was significantly higher in the low-flux regenerated cellulose membrane group than in the low- or medium-flux modified cellulose and synthetic membrane group. It also tended to be higher in the high-flux synthetic membrane group than in the low- or medium-flux modified cellulose and synthetic membrane group, although the difference was not statistically significant. Because the predialytic serum IL-6 level seemed to be influenced by the duration of hemodialysis, age, and the dialysis membrane characteristics, a multiple-regression analysis was applied to obviate the factors affecting the serum IL-6 level (Table 2). Age, the duration of hemodialysis, and the regenerated cellulose membrane
Our study has shown that the serum IL-6 level was significantly correlated with major parameters indicating malnutrition, such as body weight loss and serum albumin level. When the nutritional parameters were compared between those patients with high IL-6 (⬎10 pg/mL) and those with low IL-6 (⬍10 pg/mL), the association of IL-6 with nutrition was more pronounced. The body weight loss, which is a dynamic parameter of nutrition and is recognized as a predictor of mortality in many studies,25-27 was more than 4% Table 2. Multiple-Regression Analyses of the Effect of Age, the Duration of Hemodialysis, Characteristics of the Dialysis Membrane, and the Flux of the Dialysis Membrane Upon Subjecting 45 Chronic Dialysis Patients to Predialytic Serum IL-6 Independent Variable
Coefficient
SE
Duration of dialysis Regenerated cellulose Age High flux
0.080 0.887 0.030 0.444
0.025 0.321 0.011 0.366
t-value P Value
3.21 2.75 2.69 1.21
0.0026 0.0087 0.0103 0.2328
NOTE. Multiple r ⫽ 0.607, F ⫽ 5.82, P ⫽ 0.0009. Abbreviations: coefficient, partial regression coefficient; SE, standard error.
IL-6 AND MALNUTRITION IN HEMODIALYSIS
over the preceding 3 years in those patients with high IL-6, whereas the patients with low IL-6 did not lose weight. In those patients with high IL-6, MAMA and serum creatinine were significantly lower than those in the patients with low IL-6, suggesting that IL-6 mediated muscle loss. In addition, the patients with high IL-6 had significantly lower serum albumin and cholinesterase levels than the patients with low IL-6. Because body weight change and serum albumin are late indices of malnutrition, we measured the more rapid and sensitive indicators of protein nutrition, prealbumin and IGF-1. Prealbumin and IGF-1 also tended to be lower in the patients with high IL-6 than in those with low IL-6. This collective evidence suggests that serum IL-6 level was associated with the nutritional disturbance in the chronic hemodialysis patients. IL-6 mediates the acute-phase response, which was characterized by an increased synthesis of acute-phase reactants including CRP, fibrinogen, and amyloid A protein, and by a reduced synthesis of albumin and transferrin by hepatocytes.16 IL-6 is considered to act synergistically with TNF-␣ and IL-1 to downregulate albumin mRNA and thus inhibit albumin synthesis.28 In fact, serum IL-6 was positively correlated with CRP and sialic acid and showed inverse correlation with serum albumin in our study. Kaysen et al15 have shown that the rate of albumin synthesis was negatively correlated with ␣2-macroglobulin, a carrier protein of IL-6, and that the serum albumin concentration was inversely correlated with acute-phase proteins, ␣2-macroglobulin, CRP, and ferritin by a multiple-regression analysis. These findings support IL-6 being associated with suppressed albumin synthesis in chronic hemodialysis patients. Furthermore, IL-6 has been known to stimulate muscle proteolysis in many chronic neoplastic or inflammatory diseases.17,18 Although other cytokines such as IL-1 and TNF have been reported to be involved in muscle protein catabolism, IL-6 appeared to have a more significant role than TNF in mediating cancer cachexia.19 The evidence that MAMA and serum creatinine in the high–IL-6 patients was lower than that in the low–IL-6 patients in our study supports the effect of IL-6 on muscle protein catabolism in chronic dialysis patients.
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Cytokines have also been reported to suppress appetite, by which malnutrition might be accelerated.29 With our cases, however, there was no difference in PCR, an indicator of dietary protein intake under stable conditions, between the patients with a high IL-6 and those with a low IL-6 level. The serum IL-6 level measured by either a bioassay20,21 or enzyme-linked immunosorbent assay (ELISA22) has been reported to increase in patients with chronic renal failure. Hemodialyzed patients in particular have shown a higher level of IL-6 than CAPD patients or uremic patients without dialysis, suggesting that hemodialysis stimulated IL-6 production.22 The reports comparing IL-6 between prehemodialysis and posthemodialysis indicated that serum IL-6 did not increase during a hemodialysis session if the postdialysis IL-6 value was corrected by the ultrafiltrate volume.20 However, the plasma IL-6 level had significantly increased within a few hours after the end of the dialysis session, a time consistent with the activation of monocytes.20 An increased expression of IL-6 mRNA in peripheral blood mononuclear cells (PBMC) was found in patients undergoing hemodialysis in comparison with healthy controls, and a further increase was detected during a hemodialysis session.30 This collective evidence suggests that the high IL-6 level in hemodialyzed patients was attributable to the stimulation of monocytes by the hemodialysis. Proposed mechanisms for stimulating monocytes and releasing IL-6 production during hemodialysis include blood interaction with the hemodialysis membrane and backleakage of endotoxin from the contaminated dialysate through a high-flux dialysis membrane.31 Another possibility for the increase of serum IL-6 level in chronic dialysis patients is due to superimposed illnesses. One of the important illnesses that complicate hemodialysis is dialysisrelated amyloidosis. Miyata et al32 have recently reported that advanced glycosylation productmodified 2-microglobulin, which has been recognized as the major precursor protein of dialysisrelated amyloidosis, enhanced chemotaxis and chemokinesis of human monocytes and enhanced the secretion of cytokines. This fact suggests the possibility that patients with dialysisrelated amyloidosis would have a high serum
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IL-6 level. In fact, it has been reported that long-term hemodialysis patients complicated with dialysis-related amyloidosis attained a high serum IL-6 level.33 However, it cannot be discounted that other chronic illnesses that induce an inflammatory response might also influence the serum IL-6 level. The incidence of dialysis-related amyloidosis is related to the duration of hemodialysis and age. A close relationship has been found between the duration of dialysis and the prevalence of amyloid deposition in the synovial and juxtaarticular bone.34 The symptoms of dialysisrelated amyloidosis seem to occur sooner after the start of hemodialysis as age advances.35 Based on all of this evidence, we applied a multipleregression analysis to elucidate the contribution of membrane characteristics, membrane flux, duration of hemodialysis, and age on the serum IL-6 level. The results show that serum IL-6 was dependent on the age, duration of hemodialysis, and the use of a regenerated cellulose membrane. The use of a regenerated cellulose membrane was associated with the increase in serum IL-6 level from the results of this study. However, there is still controversy as to whether the biocompatibility of the dialysis membrane is related to IL-6 production. PBMC of uremic patients who had been regularly hemodialyzed with a cuprophane dialyzer produced a higher amount of IL-6 than PBMC of patients dialyzed with a PMMA dialyzer.36 A similar result for monocyte IL-6 release was obtained after an in vitro stimulation of whole blood with 10 ng/mL lipopolysaccharides.37 Previous in vivo studies in which a bioassay of IL-6 was conducted, however, have failed to show any difference in the serum IL-6 level between cellulosic membranes and synthetic membranes.20,22 On the contrary, we could detect a difference in serum IL-6 level between those patients dialyzed with a regenerated cellulose membrane and those dialyzed with a modified cellulose or synthetic membrane, apart from a high-flux dialyzer. Both of the previous studies20,22 compared the predialytic IL-6 level between patients treated with cellulosic membranes and polyacrylonitrile (PANAN69) membranes. Although UFR for the two membranes was not stated in the articles, it is possible that the use of a high-flux PAN mem-
KAIZU ET AL
brane might increase IL-6 to the level of the cellulosic membrane users, as shown in our study. It has been reported that the biocompatibility of a dialysis membrane might have an impact on the nutritional status of chronic dialysis patients. Parker et al38 have reported that a biocompatible dialysis membrane has a favorable effect on nutritional status in comparison with a bioincompatible membrane. In their prospective study, patients dialyzed with a biocompatible membrane underwent an increase in dry weight of more than 4 kg over 18 months and a rapid increase in IGF-1 and serum albumin, whereas the patients dialyzed with a bioincompatible membrane showed no change in body weight and serum albumin. More recently, Hakim et al39 have shown that the relative risk of mortality to patients dialyzed with a modified cellulose or synthetic membrane was at least 20% less than that to patients treated with an unsubstituted cellulose membrane. Combining our data with these results, the use of a biocompatible membrane dialyzer might provide great benefits to chronic hemodialysis patients. The results of this study suggest that the serum IL-6 level is one of the relevant factors for nutritional status in chronic dialysis patients. The patients with a high serum IL-6 level had lost body weight over the preceding 3 years and had lower serum albumin and cholinesterase levels than the patients with a low serum IL-6 level. The duration of dialysis, age, and the use of a regenerated cellulose membrane were related to the serum IL-6 level. ACKNOWLEDGMENT The authors thank A.K.J. Innes and Akihito Morita for helpful advice in preparing the manuscript.
REFERENCES 1. Bergstro¨m J: Nutrition and mortality in hemodialysis. J Am Soc Nephrol 6:1329-1341, 1995 2. Ikizler TA, Hakim RM: Nutrition in end-stage renal disease. Kidney Int 50:343-357, 1996 3. Acchiardo SR, Moore LW, Latour PA: Malnutrition as the main factor in morbidity and mortality of hemodialysis patients. Kidney Int 24:S199-S203, 1983 (suppl) 4. Goldwasser P, Mittman N, Antignani A, Burrell D, Michel M, Collier J, Avram MM: Predictors of mortality in hemodialysis patients. J Am Soc Nephrol 3:1613-1622, 1993
IL-6 AND MALNUTRITION IN HEMODIALYSIS
5. Borah MF, Schoenfeld PY, Gotch FA, Sargent JA, Wolfson M, Humphreys MH: Nitrogen balance during intermittent dialysis therapy of uremia. Kidney Int 14:491500, 1978 6. Lim VS, Flanigan MJ: The effect of interdialytic interval on protein metabolism: Evidence suggesting dialysisinduced catabolism. Am J Kidney Dis 14:96-100, 1989 7. Hara Y, May RC, Kelly RA, Mitch WE: Acidosis, not azotemia, stimulates branched-chain amino acid catabolism in uremic rats. Kidney Int 32:808-814, 1987 8. Reaich D, Channon SM, Scrimgeour CM, Daley SE, Wilkinson R, Goodship THJ: Correction of acidosis in humans with CRF decreases protein degradation and amino acid oxidation. Am J Physiol 265:E230-E235, 1993 9. Bergstro¨m J: Nutritional requirements of hemodialysis patients, in Mitch WE, Klahr S (eds): Nutrition and the Kidney. Boston, MA, Little, Brown, 1993, pp 263-289 10. Kopple JD, Swendseid ME, Shinaberger JH, Umezawa CY: The free and bound amino acids removed by hemodialysis. Trans Am Soc Artif Internal Organs 19:309-313, 1973 11. Ikizler TA, Flakoll PJ, Parker RA, Hakim RM: Amino acid and albumin losses during hemodialysis. Kidney Int 46:830-837, 1994 12. Gutierrez A, Alvestrand A, Wahren J, Bergstro¨m J: Effect of in vivo contact between blood and dialysis membranes on protein catabolism in humans. Kidney Int 38:487-494, 1990 13. Gutierrez A, Bergstro¨m J, Alvestrand A: Protein catabolism in sham-hemodialysis: The effect of different membranes. Clin Nephrol 38:20-29, 1992 14. Hakim RM: Clinical implications of hemodialysis membrane biocompatibility. Kidney Int 44:484-494, 1993 15. Kaysen GA, Rathore V, Shearer GC, Depner TA: Mechanisms of hypoalbuminemia in hemodialysis patients. Kidney Int 48:510-516, 1995 16. Le J, Vilcek J: Interleukin 6: A multifunctional cytokine regulating immune reactions and the acute phase protein response. Lab Invest 61:588-602, 1989 17. Goodman MN: Interleukin-6 induces skeletal muscle protein breakdown in rats. Proc Soc Exp Biol Med 205:182185, 1994 18. Tsujinaka T, Fujita J, Ebisui C, Yano M, Kominami E, Suzuki K, Tanaka K, Katsume A, Ohsugi Y, Shiozaki H, Monden M: Interleukin-6 receptor antibody inhibits muscle atrophy and modulates proteolytic systems in interleukin-6 transgenic mice. J Clin Invest 97:244-249, 1996 19. Strassmann G, Fong M, Kenney JS, Jacob CO: Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J Clin Invest 89:1681-1684, 1992 20. Herbelin A, Uren˜a P, Nguyen AT, Zingraff J, Descamps-Latscha B: Elevated circulating levels of interleukin-6 in patients with chronic renal failure. Kidney Int 39:954-960, 1991 21. Nakahama H, Tanaka Y, Shirai D, Miyazaki M, Imai N, Yokokawa T, Okada M, Kubori S: Plasma interleukin-6 levels in continuous ambulatory peritoneal dialysis and hemodialysis patients. Nephron 61:132-134, 1992 22. Cavaillon JM, Poignet JL, Fitting C, Delons S: Serum
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interleukin-6 in long-term hemodialyzed patients. Nephron 60:307-313, 1992 23. Daugirdas JT: Second generation logarithmic estimates of single pool variable volume of Kt/V: An analysis of error. J Am Soc Nephrol 4:1205-1213, 1993 24. Bergstro¨m J, Wehle B: No change in corrected 2-microglobulin concentration after cuprophan hemodialysis. Lancet 1:628-629, 1987 25. Lee IM, Paffenbarger RS: Change in body weight and longevity. JAMA 268:2045-2049, 1992 26. Pamuk ER, Williamson DF, Serdula MK, Madans J, Byers TE: Weight loss and subsequent death in a cohort of US adults. Ann Intern Med 119:744-748, 1993 27. Andres R, Muller DC, Sorkin JD: Long-term effects of change in body weight on all-cause mortality: A review. Ann Intern Med 119:737-743, 1993 28. Andus T, Geiger T, Hirano T, Kishimoto T, Heinrich PC: Action of recombinant human interleukin 6, interleukin 1 and tumor necrosis factor ␣ on the mRNA induction of acute-phase proteins. Eur J Immunol 18:739-746, 1988 29. Moldawer LL, Andersson C, Gelin J, Lundholm KG: Regulation of food intake and hepatic protein synthesis by recombinant-derived cytokines. Am J Physiol 254:G450G456, 1988 30. Pertosa G, Gesualdo L, Tarantino EA, Ranieri E, Bottalico D, Schena FP: Influence of hemodialysis on interleukin-6 production and gene expression by peripheral blood mononuclear cells. Kidney Int 43:S149-S153, 1993 (suppl) 31. Sundaram S, Barrett TW, Meyer KB, Perrella C, Neto MC, King AJ, Pereira JG: Transmembrane passage of cytokine-inducing bacterial products across new and reprocessed polysulfone dialyzers. J Am Soc Nephrol 7:21832191, 1996 32. Miyata T, Inagi R, Iida Y, Sato M, Yamada N, Oda O, Maeda K, Seo H: Involvement of beta 2-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 33. Takasu S, Takatsu S, Kunitomo K, Kokumai Y: Serum hyaluronic acid and interleukin-6 as possible markers of carpal tunnel syndrome in chronic hemodialysis patients. Artif Organs 18:420-424, 1994 34. Bardin T, Kuntz D, Zingraff J, Voisin MC, Zelmar A, Lansaman J: Synovial amyloidosis in patients undergoing long-term hemodialysis. Arthritis Rheum 28:1052-1058, 1985 35. van Ypersele de Strihou C, Jadoul M, Malghem J, Maldague B, Jamart J: Effect of dialysis membrane and patient’s age on signs of dialysis-related amyloidosis. Kidney Int 39:1012-1019, 1991 36. Memoli B, Libetta C, Rampino T, Canton AD, Conte G, Scala G, Ruocco MR, Andreucci VE: Hemodialysis related induction of interleukin-6 production by peripheral mononuclear cells. Kidney Int 42:320-326, 1992 37. Engelberts I, Francot GJM, Leunissen KML, Haenen
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B, Ceska M, van der Linden CJ, Burman WA: Effect of hemodialysis on peripheral blood monocyte tumor necrosis factor-␣, interleukin-6, and interleukin-8 secretion in vitro. Nephron 66:396-403, 1994 38. Parker TF III, Wingard RL, Husni L, Ikizler TA, Parker RA, Hakim RM: Effect of the membrane biocompat-
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ibility on nutritional parameters in chronic hemodialysis patients. Kidney Int 49:551-556, 1996 39. 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