interleukin-8 and Uremia

Cytokines are pluripotent pleiotropic agents that have received widespread attention over the last few years. Not surprisingly, the have also been studied in the context of continuous ambulatory peritoneal dialysis. Cytokines play a central role in this treatment modality for uremic patients, because these inflammatory mediators act upon the biological dialysis membrane, i.e. the peritoneum, while simultaneously they participate in host defense mechanisms. This review describes which cytokines are present in dialysate, whether there is support for intraperitoneal release, and under which circumstances. If focuses particularly on the relationship between cytokines in peritoneal effluent and peritoneal permeability to macromolecules. In addition, the presence of prostanoids in dialysate and their role in the local regulation of peritoneal permeability are discussed, because cyclooxygenase products are tightly linked to cytokine networks.

Topics: Animals; Cell Membrane Permeability; Cytokines; Humans; Interleukin-1; Interleukin-8; Macrophages, Peritoneal; Peritoneal Dialysis, Continuous Ambulatory; Peritoneum; Peritonitis; Prostaglandins; Tumor Necrosis Factor-alpha; Uremia

A total of 105 patients participated in this study, including 10 with chronic glomerulonephritis with normal renal function (CGN patients), 36 uraemic patients (CRF patients), 19 continuous ambulatory peritoneal dialysis patients (CAPD) without peritonitis, three CAPD patients with peritonitis, 37 patients undergoing chronic haemodialysis (HD) divided into short-term HD, 15 patients; medium-term HD, 12 patients; and long-term HD, 10 patients. IL-8 and two other proinflammatory cytokines, IL-6 and TNF alpha were tested using a specific immunoassay. IL-8, IL-6, and TNF alpha serum levels were significantly increased in patients with chronic renal failure compared to their levels in normal individuals (P < 0.0001, P < 0.05 and P < 0.0001 respectively). The most pronounced increment in IL-8, IL-6 and TNF alpha serum levels was observed in CAPD patients (P < 0.0001). CAPD patients without peritonitis showed relatively low levels of IL-8 or IL-6 in peritoneal dialysate effluents (PDE), whereas PDE-TNF alpha were not detectable in almost all patients tested. Patients with peritonitis showed very high serum and PDE levels of IL-8, IL-6 and TNF alpha. The clinical recovery from peritonitis was characterized by a rapid fall in IL-8, IL-6 and TNF alpha in serum and dialysate. HD patients showed a significant increase in serum levels of IL-8 and also IL-6 and TNF alpha compared to normal individuals (P < 0.05, P < 0.05 and P < 0.01 respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Chronic Disease; Female; Glomerulonephritis; Humans; Interleukin-6; Interleukin-8; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis; Renal Dialysis; Renal Replacement Therapy; Tumor Necrosis Factor-alpha; Uremia

Interleukin-8 (IL-8) has been reported to be released by activated peritoneal macrophages (PMs) and a variety of other cell types, and it exhibits potent chemotactic activity for polymorphonuclear cells (PMNs). We have previously shown that IL-8 is detectable in the drain dialysate of uremic patients on continuous ambulatory peritoneal dialysis (CAPD) during peritonitis. The levels of IL-8 in infected drain dialysate caused by different microorganisms were variable. In this study, we evaluated the gene expression and release of IL-8 by PMs and PMNs during peritonitis caused by Staphylococcus aureus in uremic patients on CAPD. IL-8 levels were variable in the drain dialysate at the different episodes of peritonitis, even in the same patient. The IL-8 levels were highly correlated with PMN count in drain dialysate (r = 0.9919, p < 0.001). PMs and PMNs obtained from drain dialysate at the onset of peritonitis increased mRNA expression for IL-8 and the amount of IL-8 mRNA from drainage cells was also highly correlated with PMN count. In contrast, cells isolated from drain dialysate without peritonitis failed to express mRNA for IL-8. These data suggest that increased expression of IL-8 may be a feature of peritonitis. The levels of IL-8 during peritonitis were not only related to the etiological microorganism but also to other unknown factor(s).

Topics: Adult; Female; Gene Expression; Humans; Interleukin-8; Kidney Failure, Chronic; Macrophages, Peritoneal; Male; Middle Aged; Neutrophils; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis; RNA, Messenger; Staphylococcal Infections; Uremia

Toll-like receptors (TLRs) play a pivotal role in pathogen recognition and subsequent cytokine synthesis by immune cells. Uremic patients have a high infectious morbidity, but it remains unclear if this arises from the defective innate immune responses related to TLRs. We studied TLR4 expression in monocytes and their intracellular cytokine synthesis in response to lipopolysaccharide (LPS) stimulation in 35 predialysis patients with chronic kidney disease (CKD) with or without predisposition to bacterial infections and 16 age-matched controls. Expression of TLR4 in unstimulated peripheral monocytes was determined by staining with anti-TLR4 antibody and analysis with flow cytometry. Monocytes were then stimulated by LPS, labeled with anti-CD14 antibody, and subjected to intracellular cytokine staining and flow cytometry. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-8 synthesis was examined in CD14(+) monocytes. TLR4 expression was constitutively diminished in CKD patients with reduced expression being more severe in those CKD patients who were predisposed to infections. Monocytes from these infection prone CKD patients exhibited significantly reduced synthesis of TNF-alpha, IL-1beta, IL-6, and IL-8 in response to LPS challenge compared with those from control subjects. The intensity of synthesis of each cytokine significantly correlated with TLR4 expression levels in monocytes (P<0.01). The capacity of monocytes to synthesize proinflammatory cytokines was significantly reduced in infection prone CKD patients, and this may possibly be due to the reduced monocyte expression of TLR4. Abnormal TLR4 expression by monocytes may play a role in the susceptibility of such patients to bacterial infections.

Topics: Aged; Bacterial Infections; Cytokines; Female; Flow Cytometry; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Lipopolysaccharide Receptors; Lipopolysaccharides; Male; Middle Aged; Monocytes; Renal Insufficiency, Chronic; Toll-Like Receptor 4; Uremia

There is still no evidence whether human peritoneal mesothelial cells (HPMC) from patients with end-stage renal failure are altered in cell viability or show a different pattern of the release of proinflammatory cytokines. Also the serum of patients with uremia may contain substances stimulating the cytokine release of HPMC.. The IL-1beta-induced IL-6/IL-8 release of HPMC from healthy donors and from patients with end-stage renal disease (ESRD) were measured before the start of chronic peritoneal dialysis (PD) and during PD therapy. Additionally the influence of uremic and non-uremic serum on IL-6 and IL-8 release of normal HPMC was studied. Cell viability was assessed by MTT assay and by the measurement of intracellular ATP (chemoluminescence assay). HPMC were obtained from the following patient groups: (1) non-uremic control patients (n = 7); (2) patients with ESRD undergoing PD catheter implantation for the first time (n = 7), and (3) patients on PD undergoing catheter exchange for noninfectious reasons (n = 6). Pooled human serum from PD patients and normal controls were used for stimulation experiments. HPMC from different donors were grown to confluence (second passage) and then stimulated with IL-1beta (1,000 pg/ml in M199) for 24 h. IL-6 and IL-8 concentrations were measured in the supernatant by ELISA. Additionally uremic and non-uremic sera were incubated with HPMC from normal donors for 24 h with a subsequent 24-hour IL-1beta stimulation. Mesothelial cell protein mass was determined by the Bradford reagent.. Non-uremic patients and ESRD patients did not differ with regard to the global cell viability of HPMC according to MTT assay activity or the intracellular ATP concentration. However, HPMC from uremic patients produced more IL-8 on IL-1beta stimulation than the non-uremic controls (group 2, 53.5 +/- 15.7 pg/microg; group 3, 70.5 +/- 27.3 pg/microg vs. group 1, 24.0 +/- 11.8 pg/microg). HPMC from patients on chronic PD additionally released significantly more IL-6 (30.5 +/- 13.8 pg/microg) on IL-1beta stimulation than uremic patients before the onset of PD (6.2 +/- 2.6 pg/microg; p < 0.01). Incubation of normal HPMC with the serum from uremic donors produced an enhanced stimulated IL-8 release compared to the exposition with normal control serum (50.6 +/- 6.1 vs. 20.8 +/- 2.9 pg/microg; p < 0.01).. HPMC from uremic patients more readily release IL-8 on stimulation with IL-1beta. On chronic PD treatment IL-6 release was further enhanced. Not further classified serum components in uremia also enhance IL-6 and IL-8 release of HPMC.

Topics: Adenosine Triphosphate; Adult; Cell Survival; Cells, Cultured; Cytokines; Enzyme-Linked Immunosorbent Assay; Epithelium; Female; Humans; Immunohistochemistry; Interleukin-1; Interleukin-6; Interleukin-8; Kidney Failure, Chronic; Luminescent Measurements; Male; Middle Aged; Peritoneal Cavity; Protein Biosynthesis; Tetrazolium Salts; Thiazoles; Uremia

Priming of the polymorphonuclear neutrophil (PMN) response has been implicated in the activation of oxidative burst and tissue injury in patients with septic shock and acute renal failure (ARF). This study evaluated whether hemofiltration (HF) removes substances able to enhance the oxidative burst of PMNs.. Chemiluminescence (CL) priming activity induced by sera and ultrafiltrates of seven patients with septic shock, multiorgan dysfunction syndrome, and ARF (ARF/HF group) and of 10 uremic stable patients (Control/HF group) was evaluated on normal human PMNs stimulated with bacterial formyl-methionyl-leucyl-phenylalanine (FMLP). Patients submitted to HF were studied by determining blood and ultrafiltrate interleukin-8 (IL-8), platelet-activating factor (PAF), and CL priming activity at the beginning (T0), and after four hours (T4) of treatment.. Preincubation of normal human PMNs with sera and ultrafiltrates from septic patients induced a potent priming of CL activity in subsequent FMLP stimulation. In the ARF/HF group, the prefilter blood concentrations of IL-8 and CL PMN-priming activity significantly decreased during the four hours of HF treatment, with a loss of IL-8 in the ultrafiltrate of 6930 (median, range 4292 to 9282) ng per four hours. PAF detected in the ultrafiltrate and associated with the membrane (7.3 ng, range 1.45 to 9.89) was minimal. In the ARF/HF group, a significantly positive correlation between CL PMN-priming activity and IL-8 concentrations was observed. The CL priming activity in blood and ultrafiltrates was reduced to 55 and 46% by preabsorption with monoclonal antibody (mAb) anti-IL-8. In contrast, the PAF receptor antagonist WEB 2170 did not affect CL priming activity. In the control/HF group, the CL PMN-priming activity was significantly lower than in the ARF/HF group and was independent of IL-8.. Sera from septic patients demonstrate an enhanced CL priming activity on PMNs. This activity is reduced by ultrafiltration and is due, at least in part, to ultrafiltered IL-8.

Topics: Acute Kidney Injury; Aged; Blood Physiological Phenomena; Hemofiltration; Humans; Interleukin-8; Luminescent Measurements; Middle Aged; Multiple Organ Failure; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Platelet Activating Factor; Reference Values; Respiratory Burst; Shock, Septic; Uremia

Uremia produces a wide range of abnormalities of the immune system. Blood-membrane interaction in hemodialysis results in activation and severe dysfunction of peripheral blood mononuclear cells (PBMC). However, the question of whether the use of different dialytic membranes may improve PBMC dysfunctions remains unanswered.. To address this issue, the spontaneous interleukin (IL)-6, IL-8 and monocyte chemotactic peptide-1 (MCP-1) gene expression and protein release were studied in PBMC isolated from 7 healthy subjects, 8 uremic patients on conservative therapy and 8 uremic patients undergoing subsequent one month periods of hemodialysis with cuprophan (CU) and high-flux noncomplement activating membranes, polymethylmethacrylate (PMMA) and polyamide (PA). At the end of each period of treatment, PBMC were harvested at the beginning (T0) and after 180 minutes of dialysis (T180), and then were cultured in complete medium. IL-6, IL-8 and MCP-1 mRNA expression were studied by RT-PCR. In addition, MCP-1 gene expression was evaluated also by in situ hybridization. Cytokines released in the supernatant were measured by ELISA.. Compared to the control group, PBMC from uremic patients on conservative therapy and treated by CU showed a clear reduction in the cytokine release, while PMMA and PA membranes were able to normalize IL-6, IL-8 and MCP-1 protein concentration, which had been reduced by CU treatment. Interestingly, at T0, mRNA expression for all three cytokines was increased in the patients treated by CU, when compared to the control group and the uremic patients on conservative therapy. A further up-regulation was observed at T180. PMMA and PA treatment, despite increasing the cytokine secretion, significantly reduced the dialysis-induced cytokine gene expression.. PBMC exposure to CU membranes results in cytokine mRNA overexpression associated with a paradoxically reduced protein release. In contrast, long-term hemodialysis with synthetic high-flux membranes reduces IL-6, IL-8 and MCP-1 gene expression and improves the ability of PBMC to secrete these cytokines. The reduced cytokine secretion during bioincompatible dialysis may reflect a PBMC adaptation that protects uremic patients against the inflammatory effects of persistent cytokine release.

Topics: Adult; Chemokine CCL2; Female; Humans; Interleukin-6; Interleukin-8; Male; Membranes, Artificial; Middle Aged; Renal Dialysis; Transcription, Genetic; Uremia

Macrophages, predominant cells in dialysates of patients on CAPD without peritonitis, produce a wide variety of substances including cytokines. The aim of this study was to examine the cytokine production in five uninfected patients. This work investigated the presence in dialysates of interleukin-1beta, interleukin-6, interleukin-8, tumor necrosis factor alpha and the ability of peritoneal macrophages to produce these cytokines. These results were compared with values obtained from control group in non-uremic conditions (peritoneal lavage with isotonic saline or dialysis fluid). All cytokines were detectable in dialysates. Interindividual variations in cytokine concentration in dialysates were wider than variations of production of cytokines ex vivo by stimulated and unstimulated cells. In control group, dialysis fluid inhibited the cytokine production and with isotonic saline, cells produced less cytokines than dialysis patients' cells. The highest levels of interleukin-1 and tumor necrosis factor in dialysates and the highest capacity to respond to LPS were observed in patients having the shortest duration of dialysis. The variability observed did not seem to be due to cells themselves but to their environment.

Topics: Adult; Aged; Culture Media; Cytokines; Dialysis Solutions; Female; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Macrophages, Peritoneal; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Peritoneal Lavage; Tumor Necrosis Factor-alpha; Uremia

Previous studies have demonstrated that mesothelial cells (MC) are important in the local host defense system of the peritoneal cavity. Most studies on the function of MC are performed on MC derived from material of patients with normal renal function (NRF). The aim of the present study was to examine differences in interleukin (IL)-8 expression by MC from patients with NRF and from patients with end-stage renal disease (ESRD). Therefore, MC were isolated from the omentum and pleural exudate of patients with NRF, from spent effluent of stable peritoneal dialysis (PD) patients, and from omentum obtained during catheter implantation prior to PD treatment. MC were stimulated with increasing doses of IL-1 beta or tumor necrosis factor-alpha for 24 hours, after which the supernatant was analyzed for IL-8 content. The IL-8 background level of MC isolated from patients with NRF was significantly lower than the IL-8 background level of MC derived from patients with ESRD. Although IL-8 production appeared to be higher in the ESRD MC, this difference was not significant after stimulation. While the overall immunity is depressed in uremia, MC are activated. The relatively high background of IL-8 might lead to an insensitivity of neutrophils by blocking the receptors and explain their impaired chemotaxis in uremia.

Topics: Adult; Aged; Cells, Cultured; Epithelium; Female; Humans; Immune Tolerance; Interleukin-8; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Peritoneal Dialysis; Peritoneum; Reference Values; Uremia

In this study, we investigated whether peritoneal dialysate interleukin-6 (IL-6) and IL-8 levels were elevated during peritonitis in continuous ambulatory peritoneal dialysis (CAPD) patients, with special reference to the high peritonitis occurrence (HPO) group. Serial measurements of IL-6 and IL-8 levels in dialysate before, during and after resolution of peritonitis were done in 13 CAPD patients with 15 episodes of peritonitis. Based on the peritonitis occurrence, 7 patients were assigned to the low peritonitis occurrence (LPO) and 6 patients to the HPO group. Marked elevation of IL-6 and IL-8 in drain dialysate occurred in the early period of peritonitis especially on the first 2 days in both groups. However, there were no significant differences between the groups in the levels of IL-6 and IL-8 in drain dialysate on the first day of peritonitis. However, the disappearance of peritoneal dialysate IL-8 level was faster in the LPO than in the HPO group. The decrease in IL-8 levels during peritonitis was faster than that of IL-6. Marked elevation of IL-6 and IL-8 in drain dialysate was found in the patient with peritonitis caused by Staphylococcus epidermidis and mixed gram-negative bacilli. Therefore, we hypothesize that when peritonitis occurs too frequently in a short period in the HPO group, more IL-6 and IL-8 have been produced in the peritoneum contributing to the ongoing peritoneal injury and/or fibrosis.

Topics: Adolescent; Adult; Dialysis Solutions; Female; Humans; Interleukin-6; Interleukin-8; Macrophages; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis; Time Factors; Uremia