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Review
. 2021 Jul 6:12:673562.
doi: 10.3389/fimmu.2021.673562. eCollection 2021.

Renal Delivery of Pharmacologic Agents During Machine Perfusion to Prevent Ischaemia-Reperfusion Injury: From Murine Model to Clinical Trials

Rossana Franzin  1 , Alessandra Stasi  1 , Marco Fiorentino  1 , Simona Simone  1 , Rainer Oberbauer  2 , Giuseppe Castellano  3 , Loreto Gesualdo  1
Affiliations
Review

Renal Delivery of Pharmacologic Agents During Machine Perfusion to Prevent Ischaemia-Reperfusion Injury: From Murine Model to Clinical Trials

Rossana Franzin et al. Front Immunol. .

Abstract

Donor organ shortage still remains a serious obstacle for the access of wait-list patients to kidney transplantation, the best treatment for End-Stage Kidney Disease (ESKD). To expand the number of transplants, the use of lower quality organs from older ECD or DCD donors has become an established routine but at the price of increased incidence of Primary Non-Function, Delay Graft Function and lower-long term graft survival. In the last years, several improvements have been made in the field of renal transplantation from surgical procedure to preservation strategies. To improve renal outcomes, research has focused on development of innovative and dynamic preservation techniques, in order to assess graft function and promote regeneration by pharmacological intervention before transplantation. This review provides an overview of the current knowledge of these new preservation strategies by machine perfusions and pharmacological interventions at different timing possibilities: in the organ donor, ex-vivo during perfusion machine reconditioning or after implementation in the recipient. We will report therapies as anti-oxidant and anti-inflammatory agents, senolytics agents, complement inhibitors, HDL, siRNA and H2S supplementation. Renal delivery of pharmacologic agents during preservation state provides a window of opportunity to treat the organ in an isolated manner and a crucial route of administration. Even if few studies have been reported of transplantation after ex-vivo drugs administration, targeting the biological pathway associated to kidney failure (i.e. oxidative stress, complement system, fibrosis) might be a promising therapeutic strategy to improve the quality of various donor organs and expand organ availability.

Keywords: DCD − donation after cardiac death; ECD − expanded donor criteria; complement system; hypothermic perfusion; machine perfusion; normothermic perfusion; renal ischemia/reperfusion; senolytic agents.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Representation of different ischemia types exposure of organs retrieved from Living Donor (LD), DBD, DCD and ECD. Organ retrieved by DCD and ECD, or DCD+ECD donors are subjected to longer warm ischemia time due to cardiocirculatory arrest, whereas in DBD surgical preparation and perfusion with cold preservation solution is initiated immediately after cerebral death. DCD, donation after circulatory death; DBD, donation after brain death; ECD, Expanded criteria donors; WIT, warm ischemia time; CIT, cold ischemia time; SCD, Standard Criteria Donors.
Figure 2
Figure 2
Molecular mechanisms of renal IRI. During ischemia, the lack of oxygen and substrates led to inhibition of oxidative phosphorylation, thereby to ATP depletion. From a side this led to an anaerobic lactic acid-associated glycolysis, with pH decrease and lysosome lytic enzyme release. From the other, the blockade of pump Na/K activated proteases and phospholipases, leading to increased Ca++ level. Furthermore, ATP produced in aerobic tissues is lysed into AMP, adenosine, inosine and hypoxanthine. Hypoxanthine is metabolized by xanthine oxidase in ischemic tissues, in a reaction that uses molecular oxygen (O2) and release toxic ROS as intermediate products. During reperfusion, DAMP released by ischemic damaged kidney cells are recognized by PRR as TLR on immune cells but also on endothelial cells leading to increased gene expression of pro-inflammatory cytokines that recruited and activated leucocytes. These cells released more cytokines, in an amplification loop culminating into ROS release by macrophages and neutrophils, interstitial infiltrates and kidney damage. Ischemic damaged cells can activate complement system (by Collectin-11, MBL) that result in anaphylotoxins C3a and C5a generation and MAC-mediated cell injury. These acute processes have been linked to early renal fibrosis development by the process of EndMT, EMT and PMT (Endothelial to mesenchymal transition, Epithelial to mesenchymal transition and Pericytes to mesenchymal transition). TLR, Toll Like receptor; MAC, membrane associated complex; DAMP, Damage-associated molecular patterns; PRR, Pattern Recognition Receptors; ROS, reactive oxygen species.
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