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      Subnormothermic Oxygenated Perfusion Optimally Preserves Donor Kidneys Ex Vivo

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          Abstract

          Introduction

          The current methods of preserving donor kidneys in nonoxygenated cold conditions minimally protect the kidney against ischemia-reperfusion injury (IRI), a major source of complications in clinical transplantation. However, preserving kidneys with oxygenated perfusion is not currently feasible due to the lack of an ideal perfusion mechanism that facilitates perfusion with blood at warm temperature. Here, we have designed an innovative renal pump circuit system that can perfuse blood or acellular oxygen carrier under flexible temperatures, pressures, and oxygenation. We have tested this apparatus to study optimal conditions of storage of our porcine model of donation after cardiac death (DCD) kidneys.

          Methods

          Porcine kidneys were retrieved after 30 minutes of cross-clamping renal pedicles in situ. Cessation of blood mimics postcardiac death in humans and simulates DCD warm ischemic injury. Procured kidneys were flushed and subjected to static cold storage (SCS) for 4 hours. For warm perfusion, kidneys were cannulated for pulsatile oxygenated perfusion with blood:PlasmaLyte for 4 hours at 15 °C, 22 °C, and 37 °C. To mimic posttransplant scenario, all kidneys were reperfused with blood for an additional 4 hours at 37 °C.

          Results

          Compared with all other groups, 22 °C perfusion resulted in significant reduction of acute tubular necrosis (ATN), apoptosis, kidney damage markers, Toll-like receptor signaling, and cytokine production. It was associated with maximal renal blood flow and urine output. Kidneys stored at 15 °C thrombosed within 2 hours under this condition. Martius Scarlet Blue staining confirmed that 22 °C was the optimal temperature to minimize hemorrhage and blood clots.

          Conclusion

          Our novel study shows that oxygenated perfusion at near-room-temperature provides optimal donor kidney storage conditions.

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          Most cited references 15

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          Delayed graft function in the kidney transplant.

          Acute kidney injury occurs with kidney transplantation and too frequently progresses to the clinical diagnosis of delayed graft function (DGF). Poor kidney function in the first week of graft life is detrimental to the longevity of the allograft. Challenges to understand the root cause of DGF include several pathologic contributors derived from the donor (ischemic injury, inflammatory signaling) and recipient (reperfusion injury, the innate immune response and the adaptive immune response). Progressive demand for renal allografts has generated new organ categories that continue to carry high risk for DGF for deceased donor organ transplantation. New therapies seek to subdue the inflammatory response in organs with high likelihood to benefit from intervention. Future success in suppressing the development of DGF will require a concerted effort to anticipate and treat tissue injury throughout the arc of the transplantation process. ©2011 The Authors Journal compilation © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.
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            Renal transplantation after ex vivo normothermic perfusion: the first clinical study.

            Ex vivo normothermic perfusion (EVNP) is a novel method of preservation that restores circulation and allows an organ to regain function prior to transplantation. The aim of this study was to assess the effects of EVNP in kidneys from marginal donors. Eighteen kidneys from extended criteria donors (ECD) underwent a period of EVNP immediately before transplantation. Kidneys were perfused with a plasma free red-cell based solution at a mean temperature of 34.6°C. The outcome of these kidneys was compared to a control group of 47 ECD kidneys that underwent static cold storage (CS). The mean donor age was 61 ± 1 years in the EVNP and 62 ± 6 years in the CS group (p = 0.520). EVNP kidneys were perfused for an average of 63 ± 16 min and all were transplanted successfully. The delayed graft function rate (DGF), defined as the requirement for dialysis within the first 7 days was 1/18 patients (5.6%) in the EVNP group versus 17/47 (36.2%) in the CS group (p = 0.014). There was no difference in graft or patient survival at 12 months (p = 0.510, 1.000). This first series of EVNP in renal transplantation demonstrates that this technique is both feasible and safe. Our preliminary data suggests that EVNP offers promise as a new technique of kidney preservation.
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              The interaction between ischemia-reperfusion and immune responses in the kidney.

              Kidney ischemia-reperfusion injury (IRI) engages both the innate and adaptive immune responses. Cellular mediators of immunity, such as dendritic cells, neutrophils, macrophages, natural killer T, T, and B cells, contribute to the pathogenesis of renal injury after IRI. Postischemic kidneys express increased levels of adhesion molecules on endothelial cells and toll-like receptors on tubular epithelial cells. Soluble components of the immune system, such as complement activation proteins and cytokines, also participate in injury/repair of postischemic kidneys. Experimental studies on the immune response in kidney IRI have resulted in better understanding of the mechanisms underlying IRI and led to the discovery of novel therapeutic and diagnostic targets.
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                Author and article information

                Contributors
                Journal
                Kidney Int Rep
                Kidney Int Rep
                Kidney International Reports
                Elsevier
                2468-0249
                22 May 2019
                September 2019
                22 May 2019
                : 4
                : 9
                : 1323-1333
                Affiliations
                [1 ]Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, London, Ontario, Canada
                [2 ]Department of Surgery, London Health Sciences Centre, London, Ontario, Canada
                [3 ]Western University, London Health Sciences Centre, London, Ontario, Canada
                [4 ]Multi Organ Transplant Program, London Health Sciences Centre, London, Ontario, Canada
                [5 ]Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, Ontario, Canada
                Author notes
                [] Correspondence: Patrick P.W. Luke, London Health Sciences, 339 Windermere Road, London, Ontario, Canada N6A 5A5. patrick.luke@ 123456lhsc.on.ca
                Article
                S2468-0249(19)30208-6
                10.1016/j.ekir.2019.05.013
                6732735
                © 2019 International Society of Nephrology. Published by Elsevier Inc.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                Categories
                Translational Research

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