Tumor necrosis factor-alpha during continuous high-flux hemodialysis in sepsis with acute renal failure

Suppressed ex vivo endotoxin (ET)-induced production of the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), in isolated mononuclear cells (PBMCs) is associated with fatal outcome in severe sepsis. PBMCs fro m surviving patients, but not those from nonsurviving patients, recover the ir capacity to produce normal amounts of TNF-alpha. We tested the influence of two modalities of continuous renal replacement therapy (CRRT) on ex viv o-induced whole-blood production of TNF-alpha and inhibitory TNF-soluble re ceptor type I (TNFsRI) in 12 patients tvith acute renal failure and sepsis (APACHE II score 22 to 30). Methods. Standard continuous venovenous hemofiltration (CVVH; 36 liters of bicarbonate substitution fluid per day) was performed in 7 patients using p olyamid hemofilters (FH66; Gambro). In an additional five patients, we perf ormed daily 18 hours of high-flux hemodialysis (CHFD) using polysulfon F60S dialyzers (Fresenius) and 75 Liters of bicarbonate dialysate using the GEN IUS(R) single-pass batch dialysis system. Samples were separated from the b lood circuit as well as from the ultrafiltrate/spent dialysate lines at the start, during, and end of treatment. Whole-blood samples were incubated wi th 1 ng/ml of ET for three hours at 37 degrees C. Ultrafiltrate or dialysat e samples were incubated with donor whole blood in the presence of ET to me asure suppressing activity in ultrafiltrate and spent dialysate. Results. At the start of CRRT, ET-induced whole-blood TNF-alpha production was suppressed to approximately 10% of that in normal controls. During CVVH , median ET-induced TNF-alpha production increased from 0.35 ng/ml at the s tart to 1.2 ng/ml at three hours, but decreased to pre-CVVH levels at the e nd of a 24-hour period. In contrast, in patients on CHFD, the median ET-ind uced TNF-alpha production was 0.5 ng/ml at the start, 1.1 ng/ml at 3 hours, 1.6 ng/ml at six hours, and 1.5 ng/ml at the end of 18 hours of treatment. The ultrafiltrate obtained after three hours of CVVH did not contain suppr essing activity. In CHFD, the spent dialysate as compared with fresh dialys ate suppressed ET-induced TNF-alpha production in donor blood by 33% throug hout the 18 hours of treatment. Whale-blood production of TNFsRI did not ch ange significantly at any time point during CVVH or CHFD. Conclusion. These data suggest that high-volume CHFD is superior to standar d CVVH in removing a suppressing factor of proinflammatory cytokine product ion. As CVVH only transiently improves TNF-alpha production, it is most lik ely that the putative suppressing factor is removed because of saturable me mbrane adsorption in CWH.In CHFD, there is a combination of adsorption and detectable diffusion into the dialysate. It remains to be shown whether a f urther increase in the volume of dialysate per day is able to not only impr ove but normalize the cytokine response and improve outcome in septic patie nts with acute renal failure.