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 C4d fragments were evaluated in 22 patients during routine acetate or bicarbonate hemodialysis using cuprophane membranes and hemodiafiltration (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 bicarbonate-cuprophane, HDF and AFB-PAN. At beginning of the dialysis increased plasma C5b-9 levels were found in patients treated by acetate or bicarbonate-cuprophane. Moreover, a rapid significant (P < 0.001) increase of C5b-9 levels occurred in both groups 15 minutes after the onset of the hemodialysis procedure with a plateau at 180 minutes. In contrast, only a slight increase in the plasma C5b-9 levels was observed in patients dialysed with HDF or AFB using PAN membranes. This increase was more pronounced with HDF at 0 minutes compared with controls. A positive linear correlation was found in all patients between C5b-9 generation and plasma Bb levels at different times in the dialysis session. The production of C4d fragment remained unchanged in all groups, indicating that C5b-9 complex generation is due to the prevalent alternative complement pathway activation. The pattern of cytokine production strictly resembled the complement system activation and C5b-9 generation. At the start of dialysis cultured monocytes from uremic patients treated with standard bicarbonate dialysis and cuprophane membranes spontaneously released a greater amount of TNFalpha compared to healthy controls. At 180 minutes spontaneous TNFalpha and IL-6 production by monocytes was significantly (P < 0.02 and P < 0.05, respectively) increased compared to predialysis levels. Treatments using high-biocompatibility membranes, such as PAN, caused only a slight increase of the cytokine production, which was almost normalized by AFB-PAN procedure. These 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 bioincompatibility; (3) C5b-9 generation is partially involved in the cytokine release from monocytes during dialysis with bioincompatible procedures. Therefore, C5b-9 complex generation may account for pathological findings observed in long-term hemodialyzed patients.