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 from surviving patients, but not those from nonsurviving patients, recover their capacity to produce normal amounts of TNF-alpha. We tested the influence of two modalities of continuous renal replacement therapy (CRRT) on ex vivo-induced whole-blood production of TNF-alpha and inhibitory TNF-soluble receptor type I (TNFsRI) in 12 patients with 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 polyamid hemofilters (FH66; Gambro). In an additional five patients, we performed daily 18 hours of high-flux hemodialysis (CHFD) using polysulfon F60S dialyzers (Fresenius) and 75 liters of bicarbonate dialysate using the GENIUS single-pass batch dialysis system. Samples were separated from the blood circuit as well as from the ultrafiltrate/spent dialysate lines at the start, during, and end of treatment. Whole-blood samples were incubated with 1 ng/ml of ET for three hours at 37 degrees C. Ultrafiltrate or dialysate samples were incubated with donor whole blood in the presence of ET to measure 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 start to 1.2 ng/ml at three hours, but decreased to pre-CVVH levels at the end of a 24-hour period. In contrast, in patients on CHFD, the median ET-induced 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 suppressing activity. In CHFD, the spent dialysate as compared with fresh dialysate suppressed ET-induced TNF-alpha production in donor blood by 33% throughout the 18 hours of treatment. Whole-blood production of TNFsRI did not change significantly at any time point during CVVH or CHFD.


CONCLUSIONS
These data suggest that high-volume CHFD is superior to standard CVVH in removing a suppressing factor of proinflammatory cytokine production. As CVVH only transiently improves TNF-alpha production, it is most likely that the putative suppressing factor is removed because of saturable membrane adsorption in CVVH. In CHFD, there is a combination of adsorption and detectable diffusion into the dialysate. It remains to be shown whether a further increase in the volume of dialysate per day is able to not only improve but normalize the cytokine response and improve outcome in septic patients with acute renal failure.
Lonnemann
G
G
Division of Nephrology, Medizinische Hochschule Hannover, Germany. GLonnemann@T-online.de
Bechstein
M
M
Linnenweber
S
S
Burg
M
M
Koch
K M
KM
D058186:Acute Kidney Injury / Q000097:blood / Q000378:metabolism* / Q000628:therapy; D015314:Dialysis Solutions / Q000494:pharmacology; D004731:Endotoxins / Q000097:blood / Q000494:pharmacology; D005260:Female; D006440:Hemofiltration / Q000379:methods; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D006435:Renal Dialysis / Q000379:methods; D018805:Sepsis / Q000097:blood / Q000378:metabolism* / Q000628:therapy; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism*
D015314:Dialysis Solutions; D004731:Endotoxins; D014409:Tumor Necrosis Factor-alpha