ANAPHYLACTOID REACTIONS DURING HEMODIALYSIS IN SHEEP ARE ACE-INHIBITOR DOSE-DEPENDENT AND MEDIATED BY BRADYKININ

Anaphylactoid reactions during hemodialysis in sheep are ACE inhibitor dose-dependent and mediated by bradykinin. Anaphylactoid reactions (A R) have been attributed to the generation of bradykinin (BK) when AN69 membranes are used together with angiotensin converting enzyme (ACE) inhibitors during hemodialysis. However, conclusive evidence for the i nvolvement of the BK as the mediator of these AR is still lacking. Thi s study examined the degree of contact activation in an animal model c aused by three PAN membranes - AN69, PAN DX, and SPAN - and the effect s of different doses of the ACE inhibitor enalapril (ENA) and the BK B -2-receptor antagonist icatibant on AR during hemodialysis. Six sheep were dialyzed for one hour with or without ENA pre-treatment using the different membranes in random order. Severe AR were observed only dur ing hemodialysis with AN69 dialyzers together with ENA pre-treatment; the severity of AR increased with the ENA dose, Mild hypotension was n oted during hemodialysis with AN69 without ACE inhibition and with PAN DX and 20 mg ENA. Compared to pre-dialysis values. maximum generation of BK after blood passage through the dialyzer was found at five minu tes: 73-fold (AN69 without ENA), 161-fold (AN69 with 10 mg ENA), 97-fo ld (AN69 with 20 mg ENA), 108-fold (AN69 with 30 mg ENA), 154-fold (AN 69 with 30 mg ENA and 0.1 mg/kg icatibant), 15-fold (PAN DX without EN A), and 42-fold (PAN DX with 20 mg ENA). Elevated BK levels in arteria l blood were detected during hemodialysis with AN69 membranes even wit hout ACE inhibition (2.5-fold); pre-treatment with 20 mg ENA further i ncreased arterial BK concentrations (4-fold). Furthermore, a marked de cline of prekallikrein and high molecular weight kininogen concentrati ons was noted for both AN69 and PAN DX membranes. Anaphylactoid reacti ons during hemodialysis were completely prevented by icatibant even af ter pre-treatment with ENA and in the presence of high BK concentratio ns. Concentrations of prekallikrein; high molecular weight kininogen, and BK remained unchanged and no AR were observed during hemodialysis with SPAN and pre-treatment with 20 mg ENA. Our findings confirm that AR during hemodialysis with the negatively charged AN69 membrane are m ediated by BK, since they can be prevented by the BK B-2-receptor anta gonist icatibant.