Can we attenuate ischaemia-reperfusion injury of allografts in a porcine left lung transplant models by adsorption of cytokines?

Abstract

Background Primary graft dysfunction resulting from ischaemia-reperfusion injury (IRI) remains a major obstacle after lung transplantation (LTx) and is associated with morbidity and mortality. Continuous release of inflammatory cytokines, due to the process of ischaemia and reperfusion, triggers a complex cascade of apoptosis and necrosis resulting in graft dysfunction. Previous studies demonstrated successful graft improvement by cytokine filtration during ex vivo lung perfusion (EVLP). We hypothesize that plasma cytokine filtration with CytoSorb® during in vivo graft perfusion immediately after implantation may attenuate IRI after left LTx in a porcine model. Materials and Methods Left porcine lung transplantation was performed with allografts preserved for 24 hours at 4 °C. In the treatment group [T] (n = 7), a veno-venous shunt was created to insert the cytokine filter (CytoSorbents, Berlin, Germany). In the sham group [S] (n = 4) the shunt was created without the filter. Haemodynamic parameters, lung mechanics, blood gases and plasma cytokines were assessed during 6-hours in vivo reperfusion. Results During 6 hours of reperfusion, significant differences in plasma pro-inflammatory cytokine (IFN-α, IFN-γ, and IL-6) concentrations were observed between [T] and [S], but surprisingly with higher plasma levels in the [T] group. Plasma concentrations of other pro-inflammatory cytokines (IL-1β, IL-12p40, IL-4, IL-6, IL-8, IFN-α, IFN-γ, and TNF-α) and anti-inflammatory cytokines (IL-10) did not find any evidence for a difference. Furthermore, our study failed to show meaningful difference in haemodynamics and blood gases. Also, no statistically significant differences were found between [T] and [S] in biopsies and wet-to-dry ratio at the end of the experiment. Conclusions In our porcine left lung transplantation model cytokine filtration did not achieve the intended effect. This is in contrast to previous studies with CytoSorb® use during ex vivo lung perfusion as a surrogate LTx model. Our findings might highlight the fact that the theoretical benefit of inserting an additional cytokine adsorber to improve graft function in clinical practice should be critically evaluated with further studies.

Extracorporeal cytokine adsorption reduces systemic cytokine storm and improves graft function in lung transplantation

“…The findings from the Leuven group 12 in a similar model showed contrasting results compared with our study and the Lund group. They observed a significant increase in mean pulmonary artery pressure and pulmonary vascular resistance, along with elevated partial pressure of carbon dioxide and high cytokine levels in the plasma.…”

“… 11 However, another study did not find a beneficial effect after 6 hours of posttransplant hemoadsorption in a pig model. 12 …”

Pharmacokinetics of immunosuppressive agents during hemoperfusion in a sheep model

“…Regarding corticosteroids, ex-vivo elimination has been shown for methylprednisolone in a lung perfusion model (31) and for cortisol in brain-dead humans (32). In contrast, in an interim analysis in patients with myocardial revascularization divided into three different groups (one of them with a hemoadsorber integrated into the CPB) all hormone levels including cortisol remained comparable between groups suggesting no clinically relevant removal by the device (15).…”

Hemoadsorption in Organ Preservation and Transplantation: A Narrative Review

“…In a large animal model, Frick uses a porcine-LuTx model and finds that continuous CA results in a significant improvement in lung graft function, as assessed by the degree of allograft injury, post-transplant survival, and blood chemistries [21]. The study also reports a significant reduction in pro-inflammatory cytokine and chemokine levels in the systemic circulation of the animals.…”