N-acetylcysteine modulates effect of the iron isomaltoside on peritoneal mesothelial cells.

Intravenous (i.v.) iron supplementation is used in patients on chronic peritoneal dialysis (pd). Iron induced intraperitoneal inflammation observed in our previous studies with iron sucrose may deteriorate the function of the peritoneum as the dialysis membrane. We evaluated effect iron compound, iron-isomaltoside-100 (IIS) on the peritoneal mesothelial cells (MC). We studied the effect of iv treatment with IIS ± N-acetylcysteine (NAC) on the dialysate parameters and function of MC. In 7 uremic pd patients IIS 200 mg was infused i.v. ± NAC 600 mg. Afterward, a 4 hours exchange was performed with Dianeal 1.5%. As a control dialysate exchange preceding IIS treatment was used. Inflammatory parameters of the drained dialysates as well as the dialysates and IIS effects on MC were evaluated in ex vivo experiments. Intravenous infusion of IIS resulted in an increase of the dialysate Fe (+147%, P < 0.01). Concentrations of the dialysates inflammatory mediators were increased: interleukin-6 (IL-6) +39%, P < 0.02, monocyte chemoattractant protein-1(MCP1) +50%, P < 0.02, and hyaluronan (HA) +64%, P < 0.02. Simultaneous i.v. infusion of NAC prevented increase of the dialysate inflammatory mediators. Dialysates collected after IIS treatment induced oxidative stress in MC (+29%, P < 0.05) and stimulated IL-6 synthesis (+64%, P < 0.05) in MC; no such effect was seen in dialysates obtained after simultaneous IIS and NAC i.v. treatment. IIS used as the additive to culture medium stimulated synthesis in MC of IL6 (+76%, P < 0.001) and plasminogen activator inhibitor-1 (PAI-1) (28%, P < 0.001) whereas synthesis of tissue plasminogen activator (t-PA) was reduced (-16%, P < 0.001). These changes were prevented in the presence of NAC 1 mmol/L. Intravenous administration of IIS results in the mild stimulation of intraperitoneal inflammation. IIS changes MC phenotype to the inflammatory one with reduced fibrinolytic activity. These effects are prevented by NAC.

Sulodexide modulates the dialysate effect on the peritoneal mesothelium.

Peritoneal membrane damage during chronic peritoneal dialysis is the main cause of that treatment failure. Preservation of the mesothelial cells (MC) is important for the survival of the peritoneum. Evaluation of dialysates effect on the function of MC and potential modification of that effect by sulodexide (heparin 80% and dermatan sulfate 20%). Dialysate effluents, after the overnight exchange with dianeal 1.5% dextrose, were collected from 7 continuous ambulatory peritoneal dialysis (CAPD) patients, and their effect ± sulodexide 0.5 LRU/mL on genes expression, secretory activity and protein synthesis in MC was studied. Exposure of MC to the studied dialysates caused intracellular oxidative stress and significantly increased expression of the genes regulating the synthesis of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), transforming growth factor-beta (TGF-ß), vascular cell adhesion molecule 1 (VCAM-1) and vascular endothelial growth factor (VEGF). Secretion of the studied molecules from MC treated with dialysates was increased: by 96% for IL-6 (P < 0.01), 34% for MCP-1(P < 0.01), 24% for TGF-ß (P < 0.01), 27% for VCAM-1 (P < 0.01), and by 15% for VEGF (P < 0.01). Sulodexide reduced the stimulatory effect of the dialysates on the intracellular generation of free radicals, genes expression and secretory activity of MC. These cells exposed to the dialysates showed increased synthesis of total protein (by 216%, P < 0.005) and collagen (by 264%, P < 0.005), as compared to standard culture medium. Supplementation of the dialysates with sulodexide resulted in weaker stimulation of collagen synthesis (-21% versus dialysate). We concluded that peritoneal dialysate changes the genes expression and phenotype of MC to a proinflammatory, profibrotic and proangiogenic one. Sulodexide reduces these negative effects of the dialysate.