Ex-vivo Kidney Machine Perfusion: Therapeutic Potential

Abstract

Kidney transplantation remains the gold standard treatment for patients suffering from end-stage kidney disease. To meet the constantly growing organ demands grafts donated after circulatory death (DCD) or retrieved from extended criteria donors (ECD) are increasingly utilized. Not surprisingly, usage of those organs is challenging due to their susceptibility to ischemia-reperfusion injury, high immunogenicity, and demanding immune regulation after implantation. Lately, a lot of effort has been put into improvement of kidney preservation strategies. After demonstrating a definite advantage over static cold storage in reduction of delayed graft function rates in randomized-controlled clinical trials, hypothermic machine perfusion has already found its place in clinical practice of kidney transplantation. Nevertheless, an active investigation of perfusion variables, such as temperature (normothermic or subnormothermic), oxygen supply and perfusate composition, is already bringing evidence that ex-vivo machine perfusion has a potential not only to maintain kidney viability, but also serve as a platform for organ conditioning, targeted treatment and even improve its quality. Many different therapies, including pharmacological agents, gene therapy, mesenchymal stromal cells, or nanoparticles (NPs), have been successfully delivered directly to the kidney during ex-vivo machine perfusion in experimental models, making a big step toward achievement of two main goals in transplant surgery: minimization of graft ischemia-reperfusion injury and reduction of immunogenicity (or even reaching tolerance). In this comprehensive review current state of evidence regarding ex-vivo kidney machine perfusion and its capacity in kidney graft treatment is presented. Moreover, challenges in application of these novel techniques in clinical practice are discussed.

Impact of Machine Perfusion on the Immune Response After Liver Transplantation – A Primary Treatment or Just a Delivery Tool

“…Others have added specific molecules during cold storage or as a treatment in the recipient. Most molecules were however not yet transferred into clinical practice, although the results seen in experimental studies appeared quite promising with impact on IRI-associated inflammation, the effect got either lost or was limited when explored in transplant models (40,57,58). The reason behind could be the target of too peripheral individual genes or molecules of the IRI-cascade.…”

“…And secondly, perfusate could be used to carry specific molecules into the cells and subcellular compounds to prevent production and release of IRI-associated compounds. Various therapies, such as pharmacological agents, genes, stem cells and nanoparticles were administered into organs through this route in preclinical studies (56,57). The technique of normothermic perfusion is more frequently applied because of the assumed better transport and uptake of such molecules at 37°C, when compared to hypothermic perfusion settings.…”

Progress and Setbacks in Translating a Decade of Ferroptosis Research into Clinical Practice

“…Thus far, efforts to prevent IRI in kidney transplantation have focused on mechanical solutions such as bridging cold ischemia time with artificial machine perfusion, successfully reducing DGF risk by ≥50% [ 73 , 74 ]. This approach should be considered an opportunity, as it is possible to use the machine perfusates as vectors for delivering medication to the organs [ 75 ]. Therefore, it appears promising to supplement perfusates with ferroptosis inhibitors to further decrease transplant damage.…”

Cold but not too cold: advances in hypothermic and normothermic organ perfusion

“…Other perfusion solutions can be used, adding different nutrients. In general, normothermic perfusion enables normal cellular metabolism, specifically when adding oxygen [ 40 ]. It could even allow repair of injuries and more sophisticated testing of functionality and viability [ 21 , 41 ].…”