A porcine model of hemodialyzer reactions: roles of complement activation and rinsing back of extracorporeal blood

Abstract

Hemodialysis reactions (HDRs) resemble complement-activation-related pseudoallergy (CARPA) to certain i.v. drugs, for which pigs provide a sensitive model. On this basis, to better understand the mechanism of human HDRs, we subjected pigs to hemodialysis using polysulfone (FX CorDiax 40, Fresenius) or cellulose triacetate (SureFlux-15UX, Nipro) dialyzers, or Dialysis exchange-set without membranes, as control. Experimental endpoints included typical biomarkers of porcine CARPA; pulmonary arterial pressure (PAP), blood cell counts, plasma sC5b-9 and thromboxane-B2 levels. Hemodialysis (60 min) was followed by reinfusion of extracorporeal blood into the circulation, and finally, an intravenous bolus injection of the complement activator zymosan. The data indicated low-extent steady rise of sC5b-9 along with transient leukopenia, secondary leukocytosis and thrombocytopenia in the two dialyzer groups, consistent with moderate complement activation. Surprisingly, small changes in baseline PAP and plasma thromboxane-B2 levels during hemodialysis switched into 30%–70% sharp rises in all three groups resulting in synchronous spikes within minutes after blood reinfusion. These observations suggest limited complement activation by dialyzer membranes, on which a membrane-independent second immune stimulus was superimposed, and caused pathophysiological changes also characteristic of HDRs. Thus, the porcine CARPA model raises the hypothesis that a second “hit” on anaphylatoxin-sensitized immune cells may be a key contributor to HDRs.

Complement-mediated dialysis reaction during regular hemodialysis treatment: a case report

“…Recently, an animal study was published, in which during routine reinfusion (rinsing blood back), a transient increase in pulmonary artery pressure (PAP) and elevation of thromboxane-B2 (TXB2) and complement levels were found. These changes were independent of the type of the dialyzer [ 11 , 12 ]. Based on the published report, we can conclude that, in our case, a CARPA reaction similar to the HSRs observed during the reinfusion experiments and described with polysulfone dialyzers probably took place.…”

“…Although we could not confirm the reaction with biochemical markers in our case, the clinical symptoms corresponded to the polysulfone dialyzer reactions described in the literature [ 8 , 13 ]. In the background of the observed reaction, a mechanism triggered by activated immune cells and mediated by the complement system can be assumed [ 11 , 12 ]. Based on our hypothesis, the immune cells circulating in the extracorporeal lines and dialyzer were potentially damaged due to hypoxia during the 3-min recirculation.…”

Lessons learned from immunological characterization of nanomaterials at the Nanotechnology Characterization Laboratory

“…Janos Szebeni of the Semmelweis University in Hungary pioneered the research on CARPA; he coined the term, described the mechanism, and developed in vitro and in vivo models used by other researchers worldwide to understand this phenomenon further and find the means for controlling it to prevent adverse health effects. Plasma complement activation and CARPA in response to pharmaceuticals, including those formulated using nanotechnology, have been extensively discussed in the literature (most recent references: ( 44 , 46 , 48 , 52 – 54 ); Dr. Szebeni published more than 100 papers on this subject). Understanding the immunogenicity of drug products and their components, as detailed in the immunogenicity section of this review, provides mechanistic insights in understanding the CARPA phenomenon due to the known role of certain types of antibodies in activating the classical complement pathway.…”

Hypersensitive Reactions During Hemodialysis Treatment: What Do We Need to Know?

“…The etiology of the hypersensitivity reaction is not always clear. Depending on severity of hypersensitive reactions, dialysis treatments may or may not be discontinued [2,3]. Hypersensitivity reaction are classified as Type A and Type B reactions [2,[4][5][6].…”