Kidney International, Vol. 42 (1992), pp. 320—326

Hemodialysis related induction of interleukin-6 production by peripheral blood mononuclear cells BRUNO MEMOLI, CARMELO LIBETTA, TERESA RAMPINO, ANTONIO DAL CANTON, GIUSEPPE CONTE, GIUSEPPE SCALA, MARIA R. RuocCo,

and VITT0RI0 E. ANDREUCCI Departments of Nephrology, 11 Faculty of Medicine, University of Naples and University of Catanzaro; Department of Nephrology, I Faculty of Medicine and Department of Biochemistry and Medical Biotechnology, II Faculty of Medicine, University of Naples, Italy

Hemodialysis related induction of interleukin-6 production by peripheral blood mononuclear cells. Interleukin-6 (IL-6) has a complex spectrum of biological activities, for example, growth and differentiation of B cells and synthesis of acute-phase proteins by the liver. To evaluate the role of this cytokine in the inflammatory response induced by blood

interaction with hemodialysis membranes, we have investigated the IL-6 synthesis and release in supernatant of 24-hour cultured peripheral blood mononuclear cells (PBMC) isolated from: (a) 10 hemodialyzed patients, (b) seven patients with advanced chronic renal failure (GFR slO mI/mm), and (c) eight healthy control subjects. In the same groups of subjects we evaluated the relationship between IL-6 synthesis and release and beta-2-microglobulin (f32m) production. Before and after dialytic treatment hemodialysis patient blood samples were drawn using the following criteria: (1) after two months of dialysis with cuprophan membranes, (2) after one and two months of dialysis with polymethylmethacrylate (PMMA) membranes, and finally, (3) after one further month of dialysis with cuprophan membranes. IL-6 was determined after 72 hours of incubation of PBMC supernatant serial dilutions with IL-6-dependent hybridoma cell line, 7TD1. Compared to IL-6 synthesis 5.6 U/3 x 106 PBMC/24 hr), hemodialyzed in control subjects (6.0

Blood interaction with hemodialysis membranes may result in the activation of circulating leucocytes and production of inflammatory cytokines [1—10]. These may account for both acute symptoms, such as fever and hypotension, and chronic disorders, such as muscle wasting, osteopenia, beta-2-microglobulin (f32m) release and amyloidosis, in hemodialyzed patients [11—18].

Several culprits have been suggested for cytokines induction during extracorporeal circulation, including complement activation [19—22], bacterial contamination of dialysate [2, 6, 7, 23, 24], leucocyte adherence [25, 26], and acetate [27]. The type of

dialysis membrane, however, seems to play a critical role because different membranes activate complement to a different extent, thus conditioning both cytokine and beta-2-microglobulin release [28—321.

In the past few years, interleukin-6 (IL-6) has emerged as a

patients, when treated with cuprophan membranes, showed signifi- monocyte/macrophage product regulating a complex spectrum cantly higher value of IL-6 production both before (23 13 U13 X 106 PBMC/24 hr) and after (26.2 11.3 U/3 x 10 PBMC/24 hr) the dialytic session. When patients were hemodialyzed with PMMA membranes, at the start of dialysis IL-6 levels were not significantly different from

values observed in healthy controls (10.6 4 U/3 x 10 PBMC/24 hr,

of functions, including bone marrow stem cell proliferation, B lymphocyte differentiation and immunoglobulin secretion, T

lymphocyte activation, acute phase protein induction, and release of other cytokines such as IL-i and TNF [33—39].

Recently, high plasma levels of IL-6 have been shown in uremic respectively). When the patients were switched back to cuprophan patients both on RDT and not yet treated with hemodialysis membranes, IL-6 production was greatly increased after one month of [40]. The specific effects of hemodialysis per se, and of different after 1 month of dialysis and 7.8 U/3 x 106 PBMC/24 hr, after 2 months,

dialysis (CU2, 44.6 9,4 U/3 x 106 PBMC/24 hr, at the start of dialysis)

reaching values significantly higher than those obtained in the first period with cuprophan membranes. No difference was observed between the values of IL-6 production obtained pre- and post-dialysis with

cuprophan or PMMA membranes. IL-6 production values in uremic non-dialyzed patients were similar to values found in control subjects (8.6 6.4 U/3 x 106 PBMC/24 hr). f32m release showed a behavior quite similar to IL-6 throughout the study, In fact, a statistically significant

dialysis membranes on IL-6 release by peripheral leucocytes, however, have not yet been defined and were the object of the present study. In addition, we investigated the relation between IL-6 production and beta-2-microglobulin leucocyte synthesis and release.

linear relationship was obtained between j32m and IL-6 values of production (r = 0.8296, P < 0.001), In conclusion, our results show higher levels of IL-6 production in hemodialyzed patients treated with cuprophan membranes, thereby suggesting a chronic stimulation. j3m production is highly related to IL-6 production; this relationship sug-

Methods

Patients and control subjects

dialysis amyloidosis.

We studied seven patients (4 male, 3 female; age 54.5 years; age range 38 to 61) with advanced chronic renal failure (GFR, evaluated with creatinine clearance 9.18 ml/min; range 7 to 10

Received for publication November 12, 1991 and in revised form March 25, 1992 Accepted for publication March 26, 1992

mi/mm) and 10 hemodialyzed (HD) patients (6 male and 4 female; age 59.4 years; range 40 to 63). For at least one year prior to the study HD patients were dialyzed with cuprophan membrane dialyzers three times a week. Five patients used a bicarbonate bath for more than one year.

gests a possible implication for this cytokine in the pathogenesis of

© 1992 by the International Society of Nephrology

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321

No patient had clinical evidence for infectious or inflamma7TDI bioassay of IL-6 tory diseases or malignancy; none was diabetic nor on steroid In agreement with other authors [401, it is well established or immunosuppressive therapy. Eight sex- and age-matched healthy volunteers were included that average sensitivity of IL-6 bioassay is about 50 to 100 times in the study as controls. greater than that of IL-6 immunoassay (ELISA). Therefore, we decided to measure IL-6 supernatant levels by IL-6 activity assay. In particular, IL-6 levels were determined by the capacDesign of the study ity to induce the proliferation of IL-6-dependent murine hybridA cross over design was used in the study. In the first phase oma cell line, (provided by Dr. J. Van Snick, Ludwig Institute of the study all patients were evaluated during dialysis with new for Cancer Research, Brussels, Belgium) [41, 42]. 7TD1 cells cuprophan membrane (Bellco Italy; membrane surface 1.0 m2; are cultured in Iscove's medium (Flow Laboratories) supplemembrane thickness 11 t; sterilization, ethylene oxide) for two mented with 10% heat-inactivated fetal calf serum (Flow Labmonths. The patients were then switched to dialysis with oratories), 1.5 mrvi L-glutamine, 0.24 mrvi L-asparagine, 0.55 polymethylmethacrylate (PMMA, Toray, Tokyo, Japan; mem- mM L-arginine, 50 /LM 2-mercaptoethanol, 0.1 mt hypoxanbrane surface 1.0 m2; membrane thickness 30 sterilization, thine, 16 LM thymidine, 50 pg/mi gentamicin, and at least 20 gamma ray) for two months; finally, they were then switched to U/mi (0.02 to 0.2 ng/ml) of human recombinant IL-6 (rIL-6, 1 x a second period of dialysis with new cuprophan membrane i07 U/ml, provided by Dr. T. Kishimoto, Division of Immunol(same filter of the first period) for one additional month. There ogy, Institute for Molecular and Cellular Biology, Osaka Uniwere no changes throughout all phases of the study in the versity, Osaka, Japan). following dialysis parameters: axial blood flow, ultrafiltration Before the assay, spent medium is removed and cells are flow rate, dialysis time and dialysate flow rate and composition washed twice with fresh medium (without IL-6) to eliminate (5 patients used bicarbonate bath and 5 patients used acetate traces of remaining IL-6. Cells are then resuspended in culture bath thorough all the study). In all dialysis sessions (during the medium (without cold thymidine and IL-6) at 20,000 cells/mi 3 phases of the study) we used the same type of blood lines and 100 d of this suspension is added to duplicate serial (PiVipOIR, BelIco Italy). dilutions of samples in the same volume. Incubation is carried During the different phases of the study patients were mea- out in 96-well, flat-bottom, gamma irradiated plates (Microtest sured two times a month, at midweek, for predialysis BUN and III, Becton Dickinson, New Jersey, USA) for 72 hours. Differserum creatinine concentrations. ent dilutions of recombinant human IL-6 are also included in the same volume of the samples (100 d) to verify the validity of the bio-assay. Blood samples 7TD1 growth factor activity was determined by measuring Blood samples (15 ml) were collected in heparinized tubes in tritiated timidine incorporation in the cells. To measure timidine controls and uremic (dialyzed and non-dialyzed) patients. In incorporation, 7TD1 cultures were pulsed with 0.5 nCi of dialyzed patients blood samples were obtained before and after [3H]-thimidine (Amersham International, London UK, specific dialytic session: at the end of the first cuprophan period (CU 1), activity 48 Ci/mmol) for the last four hours and collected by an at the end of each month of treatment with PMMA (PMMA1 automated cell harvester (Packard Micromate 196, Packard and PMMA2, respectively) and at the end of the second Instruments Company, Meriden, Connecticut, USA). Thimicuprophan period (CU2). dine incorporation in cells was determined in the samples, as IL-6 and 2m production was measured in supernatant of cpm, by a scintillation counter (Packard 1500 Tri-Carb). peripheral blood mononuclear cells (PBMC) isolated and culIL-6 activity in experimental samples was measured in U/mi. tured for 24 hours. One IL-6 unit was defined as the dilution that produces the half-maximal growth of the cells [41]. Under these conditions, the lowest detectable concentration Preparation of PBMC of IL-6 in supernatant from the zero level was 4 U/mI. SuperFifteen milliliters of whole blood were carefully layered over natant samples below this detection limit were assumed to have lymphocytes-separation medium (Flow Laboratories, Irvine, a value of 2 U/ml. This detection limit corresponds on average Scotland, UK) allowing gradient density centrifugation. Cell to 8 pg/mI, and is lower than the limits reported by others for pellets were washed twice with RPMI 1640 (Flow Laborato- commercially available immunoassays [401. ries), counted using a coulter counter and then resuspended at In our laboratory, we tested and recently reported [43] the 3 x 106/ml, in Iscove's (Flow Laboratories) containing 1% specificity of the 7TD1 response to IL-6 with an anti-IL-6 goat de-complemented fetal calf serum (Gibco), 100 lU/mi penicillin polyclonal neutralizing antibody.

(Gibco) and 100 Wml streptomycin (Gibco). On average,

PBMC contained 80% of lymphocytes and 20% of monocytes. The average percents of monocytes were not different (range 18 to 21%) in the various groups (controls, uremics, CU1, PMMA and CU2). PBMC were placed in 15 ml polypropylene round-bottom tubes (Falcon), at 37°C in a 5% CO2 saturated humidity incu-

bator. After 24 hours of incubation the supernatant was removed.

Beta-2-microglobulin assay

The quantity of /32m released by PBMC after 24 hours of incubation was determined in the supernatant by using solidphase radioimmunoassay (Abbott, Germany). The titration curve was linear from 50 to 4000 nglml, with an interassay variation of less than 3%.

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Me,noli et al: IL-6 production in hemodialyzed patients

52 -i

50

..

48-

40

32 -

30

28-

20

24-

10

I.-

0

S

CU1

PMMA1 PMMA2

CU2

Fig. 2. IL-6 production after incubating PBMC for 24 hours. Results from 10 dialyzed patients before (0) and after () dialysis session. The



S.

S...

IL-6 values were obtained at the end of the first period of dialysis with cuprophan membranes (CU!), after one (PMMA1) and two (PMMA2) months of dialysis with polymethylmethacrylate membranes and after one further month of dialysis with cuprophan membranes (CU2). IL-6 production in CU! (both pre and post dialysis) were significantly greater than in PMMAI and PMMA2 (P < 0.01). IL-6 production in CU2 were significantly greater than in CU! (P < 0.05), PMMA1 and PMMA2 (P < 0.01).

8-

4-

•S5•

Effects of different membranes. IL-6 production was different

with different membranes. Thus, the values obtained with _____________________________ C

UR

CU1

Fig. 1. IL-6 production after incubating PBMC for 24 hours. Results from 8 healthy subjects (C), 7 uremic non-dialyzed patients (UR) and 10

dialyzed patients (at the start of dialysis session, at the end of first period of dialysis with cuprophan membranes, CU 1). IL-6 production in

CUI is significantly greater than in C (P < 0.005) and UR (P < 0.05).

Statistical analysis

Stttistical analysis was carried out using the analysis of variance for repeated measures (Newman-Keuls), paired t-test and regression analysis (BMDP software). The differences were considered to be significant for P < 0.05. Results

IL-6 production Comparison among controls, uremic non-dialyzed and hemodialyzed patients. Figure 1 shows IL-6 production obtained in

PMMA membranes after one month (PMMAI = 10.6 4.0 U/3 x 106 PBMC/24 hr, at the start of dialysis) and after two months (PMMA2 = 7.8 4.4 U/3 x 106 PBMC/24 hr, at the start of dialysis) of dialysis were not different from controls and much lower than those obtained after cuprophan (Fig. 2). When the patients were switched back to the new cuprophan membrane, the IL-6 production by their PBMC in culture was greatly increased after one month of dialysis (CU2, 44.6 9.4 U/3 x 106 PBMC/24 hr, at the start of dialysis) reaching values significantly higher than those obtained with the first period with cuprophan membrane (Fig. 2).

Effect of dialytic treatment. No difference was observed between the values of IL-6 production obtained pre- and

post-dialysis with cuprophan or PMMA membranes (Fig. 2). No difference was obtained between the patients using acetate and those using bicarbonate bath.

Production of 132m in supernatant In Figure 3 the values of f32m production by PBMC are shown

for controls, non-dialyzed uremic patients and dialyzed patients. The values of f32m release were significantly greater in patients dialyzed with cuprophan membrane (CU1 and CU2) than in controls (C), uremic non-dialyzed patients (UR) and Compared to IL-6 synthesis in control healthy subjects (6.0 patients dialyzed with PMMA membranes (PMMA1 and 5.6 U13 x 106 PBMC/24 hr) and UR patients (8.6 6.4 U/3 )< PMMA2), with no difference between the values obtained 106 PBMC/24 hr), the patients usually dialyzed with new cuprophan membranes (CU 1) showed a statistically-significant before and after dialytic treatment. /32m release obtained at the end of the second cuprophan higher value of IL-6 production (23 13 U/3 x 106 PBMCI24 hr, at the start of dialysis). No difference was observed between period was significantly higher than the value obtained at the end of the first cuprophan period (Fig. 3). UR patients and control subjects. eight control subjects (C), in seven uremic non-dialyzed patients (UR) and in ten patients on RDT (at the start of dialysis session) with cuprophan membranes (CU1).

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Memoli et a!: JL-6 production in hemodialyzed patients 700

I

600 500

Fig. 3. Beta-2-microglobulin production after

incubating PBMC for 24 hours. Results in 8 control subjects (C), 7 uremic non-dialyzed patients (UR) and 10 dialyzed patients before

400

(3) and after () dialysis session at the end

300 200

I

I

100 0 C

UR

CU1

nil _______

I 9 4

__________

PMMA1 PMMA2

50

600

40

500

CU2

of the first period of dialysis with cuprophan membranes (CU1), after one (PMMAI) and two (PMMA2) months of dialysis with polymethylmethacrylate membranes and after one further month of dialysis with cuprophan membranes (CU2). Beta-2-microglobulin values in CU! (both pre- and post-dialysis) were significantly greater than in C, UR, PMMA1 and PMMA2 (P < 0.01). Beta-2microglobulin values in CU2 (both pre- and post-dialysis) were significantly greater than in CUI (P < 0.05) and C, UR, PMMAI and PMMA2 (P < 0.01).

400 x

30

300 x

20

CD

10

C

LVV 0. 100

-J

if E

0 UR

CU1

PMMA1 PMMA2

0 CU2

CU

I-.

a)

Fig. 4. Comparison between IL-6 (--0--) and beta-2-microglobulin (t) productions in uremic non-dialyzed patients (UR) and dialyzed patients (before dialysis session) at the end of first period of dialysis with cuprophan membranes (CUJ), after one (PMMAJ) and two (PMMA2) months of dialysis with polymethylmethacrylate membranes, and after one further month of dialysis with cuprophan membranes (CU2).

Relationship between IL-6 and f32m production alyzed patients during the three different periods of the study The behavior of IL-6 and that of /32m were quite similar (CU1, PMMA and CU2). throughout the study, as shown in Figure 4. A linear relation was obtained when values of /32m production were plotted against values of IL-6 production (r = 0.8296, P < 0.001; Fig. 5). Since the inclusion of several samples from the same subjects, that is, hemodialyzed patients, might influence the regres-

Discussion

In this study, we have shown that PBMC of uremic patients regularly hemodialyzed with a cuprophan dialyzer produce higher amounts of IL-6 in culture than PBMC from normal sion analysis, intercorrelations of IL-6 or /32m production subjects or non-dialyzed uremic patients. These findings clearly values for different dialysis membranes were also calculated. indicate that the interaction of PBMC with cuprophan activates No significant correlation among these values was found, PBMC and suggest that the high levels of plasma IL-6 found by confirming the independence of the observations from the same others in dialyzed patients [40] is secondary to increased in vivo subjects. production by circulating cells. Finally, no differences were observed in BUN (respectively IL-6 production was high in PBMC sampled from hemodia70.05 12.13, 72.17 14.38 and 69.20 9.17 mg/dl) and serum lyzed patients both before and after a single dialytic session, creatinine (respectively 9.28 2.57, 9.76 2.93 and 9.04 2.40 indicating that regular dialysis treatment with a cuprophan mgfdl) concentrations registered two times a month in hemodi- membrane causes prolonged activation of monocytes.

324 I-.

Memoli et a!: IL-6 production in hemodialyzed patients

1000 900

00

800

0

700

0

600

0

500

400 300

0 0

200 100

0 0

5

10 15

20

25 30

35

40 45

IL-6, U/3 x 106 PBMC/24 hr

After dialyzing the same patients for one month with PMMA, a reduction of IL-6 production by PBMC was observed, which

50 55

Fig. 5. Relationship between IL-6 and beta-2micro globulin productions in control subjects, ure,nic non-dialyzed patients and dialyzed patients, at the start of dialysis, in all phases of the study. P < 0.001; r = 0.8270; y = —1.4689

+

15.068x.

protein response during inflammation [47—52]. In humans, changes referred to acute phase proteins are characterized by

was similar to those of uremic non-dialyzed patients and decreased synthesis of albumin, modest increase in synthesis of healthy control subjects. This reduction was confirmed after two months. This effect of PMMA proves further that PMMA is more biocompatible than cuprophan, and may be accounted for by the low capacity of PMMA membranes to activate complement [29]. Recently, Vanholder et al [44] suggested that accumulation of

a number of positive acute phase proteins and, most strikingly, by dramatic increase in synthesis (up to 1000-fold or more) of

the two major acute phase proteins, C-reactive protein and serum amyloid A [49). These effects are observed also in vitro upon stimulation of hepatocytes with human rIL-6 [48, 49].

There are no studies in the literature on the effect of IL-6 uremic solutes could play a role in chronic stimulation of plasma levels in uremic patients on the release of acute phase monocytes. In our study, no differences were observed in small

proteins. We can only hypothesize that repeated inductions of acute phase proteins may cause complications mainly related to different phases of the study (when either cuprophan or PMMA amyloidosis disease, including carpal tunnel syndrome, Oswere used); these results seem to exclude any role of a different teopenia, joint fibrosis and muscle wasting [53]. Further invesaccumulation of these solutes on monocytes chronic activation. tigations with measurement of acute phase protein release in When the patients were switched back to dialysis with uremic patients are, however, needed to clarify this important cuprophan membranes a great increase of IL-6 production was issue. observed, with values significantly greater than those obtained Our results demonstrate that the production of /32m by PBMC with cuprophan before PMMA (Fig. 2). This behavior suggests is different with different types of membranes used for dialysis a more intense responsiveness of PBMC after a period of treatment (Fig. 3) and that the 132m production is related to IL-6 PMMA dialysis; such observation is consistent with that of production (Figs. 4 and 5). This relationship further suggests a Zaoui, Stone and Hakim [32], who have recently demonstrated possible implication of this cytokine in the pathogenesis of that dialysis with PMMA membranes increases HLA and f3,m dialysis amyloidosis. expression on circulating cells. It is likely that synthesis of IL-6 Interestingly, uremic non-dialyzed patients show a low 132m during the first period of dialysis with cuprophan was reduced release, as well as a low IL-6 production (Figs. 2, 3 and 4). because of the repetitive stimulation of monocytes prior to In conclusion, the production of IL-6 by PBMC of uremic testing, whereas during the second exposure to cuprophan, the patients treated with cuprophan dialyzers is increased. In monocytes had not been activated for a prolonged period of PBMC, the increased production of IL-6 is associated with time and were therefore able to up-regulate their synthesis increased 2m release. Both the abnormal IL-6 production and the increased release of J3,m are normalized after an one-month quickly. The high production of IL-6 by PBMC may have important treatment with a more biocompatible membrane. clinical implications since it is well known that elevated IL-6 plasma levels can play a role in the systemic inflammatory reaction to an infection or injury. Studies using highly sensitive Acknowledgments IL-6-dependent hybridoma growth assays show that IL-6 levels are elevated in patients who develop an acute phase response This study was partially supported by a MURST 60% grant. Part of this study was presented at the 23rd Annual Meeting of the American with changes in circulating protein levels [45, 46]. Interleukin-6 is the major regulator of the hepatic acute phase Society of Nephrology, Washington, D.C., December 2—5, 1990.

molecules (BUN and creatinine) concentrations during the

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Reprint requests to Bruno Memo/i, M.D., Department of Nephrology, ii Faculty of Medicine, University of Nap/es, Via S. Pansini 5 (EdUlcio 5), 80131, Napoli, italy.

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Hemodialysis related induction of interleukin-6 production by peripheral blood mononuclear cells.

Interleukin-6 (IL-6) has a complex spectrum of biological activities, for example, growth and differentiation of B cells and synthesis of acute-phase ...
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