The effect of electronegativity and angiotensin-converting enzyme inhibition on the kinin-forming capacity of polyacrylonitrile dialysis membranes

Abstract

The combination of negatively-charged membranes and angiotensin I-converting enzyme inhibitors (ACEi) evokes hypersensitivity reactions (HSR) during hemodialysis and bradykinin (BK)-related peptides have been hypothesized as being responsible for these complications. In this study, we tested the effects of neutralizing the membrane electronegativity (zeta potential) of polyacrylonitrile AN69 membranes by coating a polyethyleneimine layer (AN69-ST membranes) over the generation of kinins induced by blood contact with synthetic membranes. We used minidialyzers with AN69 or AN69-ST membranes in an ex vivo model of plasma and we showed that plasma dialysis with AN69 membranes led to significant BK and des-Arg(9)-BK release, which was potentiated by ACEi. This kinin formation was dramatically decreased by AN69-ST membranes, even in the presence of an ACEi, and kinin recovery in the dialysates was also significantly lower with these membranes. High molecular weight kininogen and factor XII detection by immunoblotting of the protein layer coating both membranes corroborated the results: binding of these proteins and contact system activation on AN69-ST membranes were reduced. This ex vivo experimental model applied to the plasma, dialysate and dialysis membrane could be used for the characterization of the kinin-forming capacity of any biomaterial potentially used in vivo in combination with drugs which modulate the pharmacological activity of kinins.

AN69: Evolution of the World’s First High Permeability Membrane

“…This was achieved by neutralizing the surface in contact with blood by ionic grafting of a polycationic polymer, polyethyleneimine (PEI). The result was validated by showing a corresponding reduction of the surface electrical potential, the ζ potential [25] and the absence of contact phase activation [24]. The modified membrane has been named AN69ST, with ST standing for surface treated.…”

“…After thorough investigations it appeared that the combined use of the AN69 membrane and ACE inhibitors, at the time a novel group of antihypertensive drugs, can lead to these reactions. The negatively charged membrane triggered activation of factor XII which via several steps resulted in formation of bradykinin, the normal breakdown of which was prevented by the drug-induced inhibition of the converting enzyme [24].…”

Bradykinin forming capacity of oversulfated chondroitin sulfate contaminated heparin in vitro

“…PKK and FXI circulate in plasma complexed with a cofactor, high-molecular-weight kininogen (HMW-kininogen). The contact of plasma with a negative surface like dextran sulfate (DxS) [10, 11], glass beads [12], or polyacrylonitrile membrane [13, 14] leads to the binding of FXII and HMW-kininogen. This binding of FXII is responsible for its auto activation.…”

Enzymatic biofinishes for synthetic textiles

“…Due to its excellent mechanical properties, stability and low cost, PAN fi nds many non-textile applications; it is used in water treatment, protein immobilization, ultrafi ltration and dialysis (Wang et al ., 2007 ;Désormeaux et al ., 2008 ;Vaidya et al ., 2004 ;Nie et al ., 2009 ). Other applications include reinforcing fi bres made from PAN homopolymer, used as asbestos replacement, and carbon fi bre precursor.…”