scholarly journals Ex-vivo Kidney Machine Perfusion: Therapeutic Potential

2021 ◽  
Vol 8 ◽  
Author(s):  
Ruta Zulpaite ◽  
Povilas Miknevicius ◽  
Bettina Leber ◽  
Kestutis Strupas ◽  
Philipp Stiegler ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Clinical Practice ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Kidney Graft ◽  
Machine Perfusion ◽  
Kidney Preservation

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.

scholarly journals Restoring Mitochondrial Function While Avoiding Redox Stress: The Key to Preventing Ischemia/Reperfusion Injury in Machine Perfused Liver Grafts?

2020 ◽  
Vol 21 (9) ◽  
pp. 3132 ◽  
Author(s):  
Julia Hofmann ◽  
Giorgi Otarashvili ◽  
Andras Meszaros ◽  
Susanne Ebner ◽  
Annemarie Weissenbacher ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Ros Production ◽  
Machine Perfusion ◽  
Redox Stress ◽  
Molecular Events ◽  
Regulate Cell Death

Mitochondria sense changes resulting from the ischemia and subsequent reperfusion of an organ and mitochondrial reactive oxygen species (ROS) production initiates a series of events, which over time result in the development of full-fledged ischemia-reperfusion injury (IRI), severely affecting graft function and survival after transplantation. ROS activate the innate immune system, regulate cell death, impair mitochondrial and cellular performance and hence organ function. Arresting the development of IRI before the onset of ROS production is currently not feasible and clinicians are faced with limiting the consequences. Ex vivo machine perfusion has opened the possibility to ameliorate or antagonize the development of IRI and may be particularly beneficial for extended criteria donor organs. The molecular events occurring during machine perfusion remain incompletely understood. Accumulation of succinate and depletion of adenosine triphosphate (ATP) have been considered key mechanisms in the initiation; however, a plethora of molecular events contribute to the final tissue damage. Here we discuss how understanding mitochondrial dysfunction linked to IRI may help to develop novel strategies for the prevention of ROS-initiated damage in the evolving era of machine perfusion.

scholarly journals In Vitro/Ex Vivo Models for the Study of Ischemia Reperfusion Injury during Kidney Perfusion

2020 ◽  
Vol 21 (21) ◽  
pp. 8156
Author(s):  
Sebastien Giraud ◽  
Raphaël Thuillier ◽  
Jérome Cau ◽  
Thierry Hauet
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Kidney Graft ◽  
Kidney Preservation ◽  
Hypothermic Machine Perfusion ◽  
Kidney Perfusion ◽  
Marginal Donors

Oxidative stress is a key element of ischemia–reperfusion injury, occurring during kidney preservation and transplantation. Current options for kidney graft preservation prior to transplantation are static cold storage (CS) and hypothermic machine perfusion (HMP), the latter demonstrating clear improvement of preservation quality, particularly for marginal donors, such as extended criteria donors (ECDs) and donation after circulatory death (DCDs). Nevertheless, complications still exist, fostering the need to improve kidney preservation. This review highlights the most promising avenues of in kidney perfusion improvement on two critical aspects: ex vivo and in vitro evaluation.

scholarly journals Ischemia-Reperfusion Injury in Marginal Liver Grafts and the Role of Hypothermic Machine Perfusion: Molecular Mechanisms and Clinical Implications

2020 ◽  
Vol 9 (3) ◽  
pp. 846 ◽  
Author(s):  
Zoltan Czigany ◽  
Isabella Lurje ◽  
Moritz Schmelzle ◽  
Wenzel Schöning ◽  
Robert Öllinger ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Organ Shortage ◽  
Machine Perfusion ◽  
Hypothermic Machine Perfusion ◽  
Critical Organ

Ischemia-reperfusion injury (IRI) constitutes a significant source of morbidity and mortality after orthotopic liver transplantation (OLT). The allograft is metabolically impaired during warm and cold ischemia and is further damaged by a paradox reperfusion injury after revascularization and reoxygenation. Short-term and long-term complications including post-reperfusion syndrome, delayed graft function, and immune activation have been associated with IRI. Due to the current critical organ shortage, extended criteria grafts are increasingly considered for transplantation, however, with an elevated risk to develop significant features of IRI. In recent years, ex vivo machine perfusion (MP) of the donor liver has witnessed significant advancements. Here, we describe the concept of hypothermic (oxygenated) machine perfusion (HMP/HOPE) approaches and highlight which allografts may benefit from this technology. This review also summarizes clinical applications and the main aspects of ongoing randomized controlled trials on hypothermic perfusion. The mechanistic aspects of IRI and hypothermic MP—which include tissue energy replenishment, optimization of mitochondrial function, and the reduction of oxidative and inflammatory damage following reperfusion—will be comprehensively discussed within the context of current preclinical and clinical evidence. Finally, we highlight novel trends and future perspectives in the field of hypothermic MP in the context of recent findings of basic and translational research.

scholarly journals Beneficial effects of end-ischemic oxygenated machine perfusion preservation for split-liver transplantation in recovering graft function and reducing ischemia–reperfusion injury

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daisuke Ishii ◽  
Naoto Matsuno ◽  
Mikako Gochi ◽  
Hiroyoshi Iwata ◽  
Tatsuya Shonaka ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Autologous Blood ◽  
Graft Function ◽  
Machine Perfusion ◽  
Perfusion System ◽  
Split Liver Transplantation ◽  
Split Liver

AbstractThis study examined the efficacy of end-ischemic hypothermic oxygenated machine perfusion preservation (HOPE) using an originally developed machine perfusion system for split-liver transplantation. Porcine split-liver grafts were created via 75% liver resection after 10 min of warm ischemia. In Group 1, grafts were preserved by simple cold storage (CS) for 8 h (CS group; n = 4). In Group 2, grafts were preserved by simple CS for 6 h and end-ischemic HOPE for 2 h (HOPE group; n = 5). All grafts were evaluated using an isolated ex vivo reperfusion model with autologous blood for 2 h. Biochemical markers (aspartate aminotransferase and lactate dehydrogenase levels) were significantly better immediately after reperfusion in the HOPE group than in the CS group. Furthermore, the HOPE group had a better histological score. The levels of inflammatory cytokines (tumor necrosis factor-α, interferon-γ, interleukin-1β, and interleukin-10) were significantly lower after reperfusion in the HOPE group. Therefore, we concluded that end-ischemic HOPE for split-liver transplantation can aid in recovering the graft function and reducing ischemia–reperfusion injury. HOPE, using our originally developed machine perfusion system, is safe and can improve graft function while attenuating liver injury due to preservation.

scholarly journals Novel Insights into the Molecular Mechanisms of Ischemia/Reperfusion Injury in Kidney Transplantation

2021 ◽  
Vol 2 (2) ◽  
pp. 191-207
Author(s):  
Davide Loizzo ◽  
Nicola Antonio di Meo ◽  
Mattia Rocco Peluso ◽  
Monica Rutigliano ◽  
Matteo Matera ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Reperfusion Injury ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Adaptive Immune Response ◽  
Tubular Atrophy ◽  
Pleiotropic Action

Ischemia reperfusion injury (IRI) is one of the most important mechanisms involved in delayed or reduced graft function after kidney transplantation. It is a complex pathophysiological process, followed by a pro-inflammatory response that enhances the immunogenicity of the graft and the risk of acute rejection. Many biologic processes are involved in its development, such as transcriptional reprogramming, the activation of apoptosis and cell death, endothelial dysfunction and the activation of the innate and adaptive immune response. Recent evidence has highlighted the importance of complement activation in IRI cascade, which expresses a pleiotropic action on tubular cells, on vascular cells (pericytes and endothelial cells) and on immune system cells. The effects of IRI in the long term lead to interstitial fibrosis and tubular atrophy, which contribute to chronic graft dysfunction and subsequently graft failure. Furthermore, several metabolic alterations occur upon IRI. Metabolomic analyses of IRI detected a “metabolic profile” of this process, in order to identify novel biomarkers that may potentially be useful for both early diagnosis and monitoring the therapeutic response. The aim of this review is to update the most relevant molecular mechanisms underlying IRI, and also to discuss potential therapeutic targets in future clinical practice.

scholarly journals Chronic Kidney Allograft Disease: New Concepts and Opportunities

2021 ◽  
Vol 8 ◽  
Author(s):  
Sergi Codina ◽  
Anna Manonelles ◽  
Maria Tormo ◽  
Anna Sola ◽  
Josep M. Cruzado
Keyword(s):  
Risk Factors ◽  
Kidney Transplantation ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Graft ◽  
Holistic View ◽  
Kidney Allograft ◽  
Number Of Patients ◽  
Modifiable Factors

Chronic kidney disease (CKD) is increasing in most countries and kidney transplantation is the best option for those patients requiring renal replacement therapy. Therefore, there is a significant number of patients living with a functioning kidney allograft. However, progressive kidney allograft functional deterioration remains unchanged despite of major advances in the field. After the first post-transplant year, it has been estimated that this chronic allograft damage may cause a 5% graft loss per year. Most studies focused on mechanisms of kidney graft damage, especially on ischemia-reperfusion injury, alloimmunity, nephrotoxicity, infection and disease recurrence. Thus, therapeutic interventions focus on those modifiable factors associated with chronic kidney allograft disease (CKaD). There are strategies to reduce ischemia-reperfusion injury, to improve the immunologic risk stratification and monitoring, to reduce calcineurin-inhibitor exposure and to identify recurrence of primary renal disease early. On the other hand, control of risk factors for chronic disease progression are particularly relevant as kidney transplantation is inherently associated with renal mass reduction. However, despite progress in pathophysiology and interventions, clinical advances in terms of long-term kidney allograft survival have been subtle. New approaches are needed and probably a holistic view can help. Chronic kidney allograft deterioration is probably the consequence of damage from various etiologies but can be attenuated by kidney repair mechanisms. Thus, besides immunological and other mechanisms of damage, the intrinsic repair kidney graft capacity should be considered to generate new hypothesis and potential therapeutic targets. In this review, the critical risk factors that define CKaD will be discussed but also how the renal mechanisms of regeneration could contribute to a change chronic kidney allograft disease paradigm.

Neutrophil-lymphocyte ratio and creatinine reduction ratio predict good early graft function among adult cadaveric donor renal transplant recipients. Single institution series

2018 ◽  
Vol 90 (2) ◽  
pp. 28-33 ◽  
Author(s):  
Piotr Hogendorf ◽  
Anna Suska ◽  
Aleksander Skulimowski ◽  
Joanna Rut ◽  
Monika Grochowska ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Univariate Analysis ◽  
Graft Function ◽  
Delayed Graft Function ◽  
Renal Transplant Recipients ◽  
Kidney Graft ◽  
Post Transplantation ◽  
Neutrophil Lymphocyte Ratio

Background Delayed graft function (DGF) is a common complication following kidney transplantation and is associated with ischemia-reperfusion injury (IRI). Lymphocytes contribute to the pathogenesis of IRI and ischemia-reperfusion related delayed graft function Materials and Methods 135 Caucasian patients received a kidney graft from deceased heart-beating organ donors. We divided patients into 2 groups- patients with the eGFR>=30 on the 21st day post-transplantation (n=36) and patients with the eGFR<30 on the 21st day post-transplantation (n=99) to assess kidney graft function. We measured the serum creatinine levels on 1st and 2nd post-transplant day and preoperative levels of monocytes, lymphocytes, platelets and neutrophils and their ratios. Results We have found statistically significant differences between the eGFR<30 and the eGFR>=30 groups in the average lnLymphocytes (0,36 +/-0,6 vs -0,016 +/-0,74 respectively p=0,004) lnNLR ( 1,27 +/-0,92 vs. 1,73+/-1,08 p=0,016) lnLMR (1,01 +/-0,57 vs. 0,73 +/-0,64 p=0,02), lnPLR (4,97 +/-0,55 vs. 5,26 +/- 0,67 p=0,023) and CCR2% (-20,20 +/- 21,55 vs. -4,29 +/- 29,62 p=0,004 . On univariate analysis, factors of lnLymphocytes >=0,22 (OR=0,331 95%CI 0,151-0,728 p=0,006), lnLMR>=1,4 (OR=0,255 95%CI 0,072-0,903 p=0,034) were associated with worse graft function while lnNLR>=1,05 (OR=2,653 95%CI 1,158-6,078 p=0,021), lnPLR>=5,15 (OR=2,536 95%CI 1,155-5,566 p=0,02) and CRR2 (OR=3,286 95% CI 1,359-7,944 p=0,008) indicated better graft function Conclusion Higher absolute lymphocyte count (lnLymphocytes) and lnLMR as well as lower lnNLR and lnPLR were associated with lower eGFR on the 21st day after kidney transplantation. On multivariate analysis CRR2 in combination with either lnLymphocytes, lnNLR or lnPLR improved the accuracy of detecting patients with poor graft function.

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