Hepatotoxic substance(s) removed by high-flux membranes enhances the positive acute phase response

Background. Acute phase proteins (APPs) are enhanced in end-stage renal dis ease patients (ESRD) requiring dialysis treatment. They are involved in a v ariety of pathologic processes like muscle proteolysis, cachexia, regulatio n of appetite, and atherosclerosis. They are predictive for mortality. APPs are not only makers but also active substances. They are mainly produced i n liver cells and are primarily, but not exclusively, regulated by proinfla mmatory cytokines. To what extent hepatic APPs are influenced by uremic tox ins is still unclear. Therefore, we investigated the effects of different u ltrafiltrates (UFs) on the synthesis of alpha (1)-acid glycoprotein (AGP) i n HepG2 cells. Methods. A cross-sectional as well as a crossover study with high-/low-flux membranes was conducted to investigate the impact of UFs on bioactivity of liver cell cultures. Metabolic activity (MTT test), cytotoxicity (lactate dehydrogenase release), and the positive APP AGP were measured in HcpG2 cel ls. Results. Cultured hepatocytes treated with UFs from high-flux membranes exh ibited a higher cytotoxicity (18.6 +/- 0.3% high-flux vs. 13.9 +/- 0.2% low -flux, P < 0.001) and a lower metabolic activity (29.3% high-flux vs. 50.3% low-flux, P < 0.001) in comparison with low-flux UFs. In addition, enhance d APP secretion could be observed under costimulatory conditions (high-flux 5.0 +/- 0.7 vs. low-flux 3.1 +/- 0.6 ng/mug protein, P < 0.05). The effect s of high- and low-Aux UFs were strongly expressed at the beginning and wer e still significantly different after 120 minutes of hemodialysis (HD) trea tment. The crossover experiments confirmed that UFs collected during high-f lux HD had a higher capacity to stimulate AGP synthesis in liver cells. Conclusion. The effects of UFs from dialysis patients demonstrate that hepa totoxic substances can be removed by dialysis. Stimulating the acute phase response UF collected during high-flux HD had a higher impact on liver cell s in comparison with low-Rus UF. These substances are putative cofactors in volved in cytokine regulation.