Activation of the kallikrein-kinin system in hemodialysis: Role of membrane electronegativity, blood dilution, and pH

Background. The kallikrein-kinin system activation by contact with a negati vely charged surface has been promulgated to be responsible for hypersensit ivity reactions. However, to explain the low frequency and heterogeneity of hypersensitivity reactions, we hypothesized that not only the electronegat ivity of the membrane, but also other physicochemical parameters could infl uence the activation of the contact phase system of plasma assessed by the measurement of kallikrein activity and bradykinin concentration. Methods. Plasma kallikrein activity using chromogenic substrate (S2302) and plasma bradykinin concentration (enzyme immune assay) were measured during the perfusion of human plasma (2.5 ml/min) through minidialyzers mounted w ith six different membranes [polyacrylonitrile (PAN) from Asahi (PANDX) and from Hospal (AN69), polymethylmethacrylate (PMMA) from Toray, cellulose tr iacetate (CT) from Baxter, cuprophane (CUP) from Akzo and polysulfone (PS) from Fresenius]. Results. A direct relationship was shown between the electronegativity of t he membrane assessed by its zeta potential and the activation of plasma dur ing the first five minutes of plasma circulation. With the AN69 membrane, t he detection of a kallikrein activity in diluted plasma but not in undilute d samples confirmed the importance of a protease-antiprotease imbalance lea ding to bradykinin release during the first five minutes of dialysis. With PAN membranes, the use of citrated versus heparinized plasma and the use of various rinsing solutions clearly show a dramatic effect of pH on the kall ikrein activity and the bradykinin concentration measured in plasma. Finall y, increasing the zeta potential of the membrane leads to a significant inc rease of plasma kallikrein activity and bradykinin concentration. Conclusions. Our in vitro experimental approach evidences the importance of the control of these physicochemical factors to decrease the activation of the contact system.