Effects of aprotinin on complement and granulocyte activation during ex vivo hemodialysis.
Hemodialysis with cellulosic membranes results in complement activation, granulocytopenia, and granulocyte activation. To further investigate the relationship between complement activation and granulocyte activation, we developed a model of ex vivo hemodialysis with blood flow, dialysate flow, and dialysate composition similar to in vivo hemodialysis. We used this model to investigate the effects of aprotinin, a potent serine protease inhibitor frequently used as an anti-inflammatory agent during cardiopulmonary bypass surgery, on both complement and granulocyte activation. Seven normal human volunteers were phlebotomized for ex vivo hemodialysis on two occasions each, one with and once without 800,000 kallikrein inhibitor units of aprotinin added to the circuit. Measurements were made of complement activation (radioimmunoassay for C3a desArg and C5a desArg), as well as granulocyte activation (flow cytometric measurements of reactive oxygen species (ROS) production, granulocyte CD11b-CD18 [MAC-1, CR3] expression, and CD62-L [L-selectin] expression). Statistically significant elevations in C3a desArg levels occurred by 10 minutes and reached a maximum of 5,367 +/- 712 ng/mL by 60 minutes after the initiation of ex vivo hemodialysis. Plasma C5a levels were elevated to 236 +/- 32 ng/mL at 60 minutes compared with 45 +/- 15 ng/mL predialysis. Aprotinin was able to significantly inhibit dialysis-induced C3a generation (peak 2,456 +/- 572 ng/mL at 60 minutes) as well as C5a generation (86 +/- 23 ng/mL at 60 minutes). During ex vivo hemodialysis, there was also a significant increase in granulocyte ROS production, MAC-1 upregulation, and L-selectin downregulation. Changes in granulocyte activation were not affected by the administration of aprotinin.(ABSTRACT TRUNCATED AT 250 WORDS)
Himmelfarb
J
J
Division of Nephrology, Maine Medical Center, Portland 04102.
Holbrook
D
D
McMonagle
E
E
D007611:Aprotinin / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000032:analysis; D003167:Complement Activation / Q000187:drug effects*; D005112:Extracorporeal Circulation; D006098:Granulocytes / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D019041:L-Selectin; D007958:Leukocyte Count; D016177:Macrophage-1 Antigen / Q000032:analysis; D008955:Models, Cardiovascular; D017382:Reactive Oxygen Species / Q000032:analysis; D006435:Renal Dialysis
D015815:Cell Adhesion Molecules; D016177:Macrophage-1 Antigen; D017382:Reactive Oxygen Species; D019041:L-Selectin; D007611:Aprotinin