C5B-9 GENERATION AND CYTOKINE PRODUCTION IN HEMODIALYZED PATIENTS

The role of the complement system in the induction of cytokine release is controversial. Plasma terminal C complex C5b-9 along with Bb and C 4d fragments were evaluated in 22 patients during routine acetate or b icarbonate hemodialysis using cuprophane membranes and hemodiafiltrati on (HDF) or acetate-free-biofiltration (AFB) using polyacrylonitrile ( PAN) membranes. In a subgroup of six uremic patients we also evaluated the release of tumor necrosis factor (TNFalpha) and interleukin-6 (IL -6) from monocytes before and after six subsequent sessions with bicar bonate-cuprophane, HDF and AFB-PAN. At beginning of the dialysis incre ased plasma C5b-9 levels were found in patients treated by acetate or bicarbonate-cuprophane. Moreover, a rapid significant (P < 0.001) incr ease of C5b-9 levels occurred in both groups 15 minutes after the onse t of the hemodialysis procedure with a plateau at 180 minutes. In cont rast, only a slight increase in the plasma C5b-9 levels was observed i n patients dialysed with HDF or AFB using PAN membranes. This increase was more pronounced with HDF at 0 minutes compared with controls. A p ositive linear correlation was found in all patients between C5b-9 gen eration and plasma Bb levels at different times in the dialysis sessio n. The production of C4d fragment remained unchanged in all groups, in dicating that C5b-9 complex generation is due to the prevalent alterna tive complement pathway activation. The pattern of cytokine production strictly resembled the complement system activation and C5b-9 generat ion. At the start of dialysis cultured monocytes from uremic patients treated with standard bicarbonate dialysis and cuprophane membranes sp ontaneously released a greater amount of TNFalpha compared to healthy controls. At 180 minutes spontaneous TNFalpha and IL-6 production by m onocytes was significantly (P < 0.02 and P < 0.05, respectively) incre ased compared to predialysis levels. Treatments using high-biocompatib ility membranes, such as PAN, caused only a slight increase of the cyt okine production, which was almost normalized by AFB-PAN procedure. Th ese results clearly show that: (1) complement activation occurs during routine dialysis with cellulosic membranes and leads to C5b-9 complex generation; (2) C5b-9 complex is a stable and reliable marker of bioi ncompatibility; (3) C5b-9 generation is partially involved in the cyto kine release from monocytes during dialysis with bioincompatible proce dures. Therefore, C5b-9 complex generation may account for pathologica l findings observed in long-term hemodialyzed patients.