APPEARANCE OF TUMOR-NECROSIS-FACTOR-ALPHA AND SOLUBLE TNF RECEPTOR-I AND RECEPTOR-II IN PERITONEAL EFFLUENT OF CAPD

Dialysate and serum concentrations of tumor necrosis factor-alpha (TNF -alpha), soluble TNF-receptor I (sTNFRI) and soluble TNF-receptor II ( sTNFRII) were measured during stable and infectious CAPD to determine whether these mediators are released intraperitoneally or derived from the circulation. Dialysate/serum ratios were compared to those of var ious marker proteins for peritoneal transport and to interleukin-6 (lL -6), which is locally produced. Peritoneal immunoreactive TNF-alpha co uld be detected in 19 of 20 stable CAPD patients after a night dwell, but only occasionally and in lower concentrations during and after a s tandard four-hour peritoneal permeability test. Both sTNFRs highly exc eeded TNF-alpha dialysate concentrations. In case of peritonitis a med ian 16-fold increase in dialysate TNF-alpha occurred on the first day, which declined towards control values during a longitudinal follow-up of eight consecutive days. sTNFRI and sTNFRII in dialysate increased three- to fourfold. Their peaks, however, appeared on the second perit onitis day. Bioactive TNF-alpha was only detected when immunoreactive levels exceeded 1000 pg/ml. Serum values of all variables were not alt ered during infection; sTNFRs exceeded TNF-alpha 300- to 400-fold. Dur ing stable CAPD indirect evidence was obtained for transperitoneal tra nsport from plasma to dialysate of TNF-alpha (molecular wt 17 kD), sTN FRI (55 kD) and sTNFRII (75 kD). Dialysate/serum (D/S) ratios were hig her, the lower the molecular weight; they were related to D/S ratios o f those marker proteins with the nearest molecular weight; D/S ratios were unrelated to the intraperitoneally produced IL-6. Furthermore, th e observed D/S ratios were as expected theoretically for their molecul ar weights. Higher than expected D/S ratios were found during peritoni tis for TNF-alpha on days 1 and 2, and for sTNFRII on day 2, pointing to local release within the peritoneal cavity only in the acute inflam matory phase. Gel permeation chromatography revealed that TNF-alpha wa s present in a monomeric 17 kD form, unbound to receptors, whereas in case of peritonitis smaller sTNFRII fragments, transported at a higher rate, could not be excluded. Therefore, these higher than expected D/ S ratios indicate local production of TNF-alpha during peritonitis and possibly also of sTNFRII, although transport of smaller receptor frag ments might also occur.