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Molecular Frontiers in Transplantation-Induced Ischemia Reperfusion Injury

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 16332

Special Issue Editor

1. Faculté de Médecine et de Pharmacie, Université de Poitiers, F-86000 Poitiers, France
2. Inserm U1082, F-86000 Poitiers, France
3. CHU Poitiers, Service de Biochimie, F-86021 Poitiers, France
Interests: ischemia reperfusion; organ preservation; organ quality; acute and chronic kidney injury
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Organ transplantation is the best therapy to treat organ failure. However, ischemia reperfusion injury (IRI) is unavoidable in transplantation and has a wide depth of consequences at the cellular and molecular level due to the high energy need of the tissues. This syndrome is a key therapeutic target to improve organ quality and decrease transplantation-related acute and chronic injury, a serious complication which without an efficient curative approach will shift toward graft loss.

The medical community is thus in need of novel insights to better understand the molecular mechanisms and therapies of IRI, the necessary basis on which to develop novel approaches to better manage the transplantation process and improve outcome.

I am pleased to invite all of you to participate to this Special Issue, “Molecular Frontiers in Transplantation-Induced Ischemia Reperfusion Injury”, by presenting your most recent research or ideas on improvement of transplantation-related ischemia reperfusion injury and related disorders. Experimental papers, up-to-date review articles, and commentaries are all welcome.

Dr. Raphael Thuillier
Guest Editor

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Keywords

  • ischemia reperfusion injury (IRI)

  • molecular mechanism
  • organ failure

Published Papers (9 papers)

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Editorial

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3 pages, 197 KiB  
Editorial
Molecular Frontiers in Transplantation-Induced Ischemia–Reperfusion Injury
by Raphael Thuillier
Int. J. Mol. Sci. 2023, 24(4), 3450; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043450 - 09 Feb 2023
Viewed by 768
Abstract
This Special Issue aims to summarize the most up-to-date research on ischemia–reperfusion and organ transplantation [...] Full article

Research

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13 pages, 3118 KiB  
Article
A Proof-of-Concept Preclinical Study Using a Novel Thermal Insulation Device in a Porcine Kidney Auto-Transplantation Model
by Lisa Ernst, Zoltan Czigany, Pascal Paschenda, Mareike Schulz, Lukas Breuer, Janosch Kunczik, Michael Czaplik, Wenjia Liu, Decan Jiang, Uwe Klinge, Sonja Djudjaj, Peter Boor, Georg Lurje, Eiji Kobayashi and René H. Tolba
Int. J. Mol. Sci. 2022, 23(22), 13806; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232213806 - 09 Nov 2022
Cited by 5 | Viewed by 1460
Abstract
Ischemia-reperfusion injury remains a fundamental problem during organ transplantation logistics. One key technical factor is the rapid allograft rewarming during the time of vascular reconstruction in the recipient. In this pilot study, a new thermal insulation bag (TIB) for organ transplantation was used. [...] Read more.
Ischemia-reperfusion injury remains a fundamental problem during organ transplantation logistics. One key technical factor is the rapid allograft rewarming during the time of vascular reconstruction in the recipient. In this pilot study, a new thermal insulation bag (TIB) for organ transplantation was used. Insulation capacity, tissue compatibility, and usability were tested initially ex vivo on porcine kidneys (n = 24) followed by the first in vivo usage. Fourteen female German landrace pigs underwent kidney auto-transplantation after 24 h cold storage (4 °C). During the implantation process the kidney was either insulated with the new TIB, or it was not thermo-protected at all, which represents the clinical standard. In this proof-of-concept study, the usability (knife-to-skin-time) and the general thermal capacity (30 min warm storage at 38 °C ex vivo p < 0.001) was shown. The clinical outcome showed significant differences in the determination of CRP and pi-GST levels. Syndecan-1 Antibody staining showed clear significant higher counts in the control group (p < 0.01) indicating epithelial damage. However, the effect on renal outcomes in not severely pre-damaged kidneys does not appear to be conclusively significant. A close follow-up study is warranted, especially in the context of marginal organs or in cases where anastomosis-times are prolonged due to surgical complexity (e.g., multiple vessels and complex reconstructions). Full article
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14 pages, 2034 KiB  
Article
Cell-Free Hemoglobin in Acute Kidney Injury after Lung Transplantation and Experimental Renal Ischemia/Reperfusion
by Robert Greite, Li Wang, Lukas Gohlke, Sebastian Schott, Kirill Kreimann, Julian Doricic, Andreas Leffler, Igor Tudorache, Jawad Salman, Ruslan Natanov, Fabio Ius, Christine Fegbeutel, Axel Haverich, Ralf Lichtinghagen, Rongjun Chen, Song Rong, Hermann Haller, Vijith Vijayan, Magnus Gram, Irina Scheffner, Faikah Gueler, Wilfried Gwinner and Stephan Immenschuhadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2022, 23(21), 13272; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113272 - 31 Oct 2022
Cited by 3 | Viewed by 1530
Abstract
Cell-free hemoglobin (CFH), a pro-oxidant and cytotoxic compound that is released in hemolysis, has been associated with nephrotoxicity. Lung transplantation (LuTx) is a clinical condition with a high incidence of acute kidney injury (AKI). In this study, we investigated the plasma levels of [...] Read more.
Cell-free hemoglobin (CFH), a pro-oxidant and cytotoxic compound that is released in hemolysis, has been associated with nephrotoxicity. Lung transplantation (LuTx) is a clinical condition with a high incidence of acute kidney injury (AKI). In this study, we investigated the plasma levels of CFH and haptoglobin, a CFH-binding serum protein, in prospectively enrolled LuTx patients (n = 20) with and without AKI. LuTx patients with postoperative AKI had higher CFH plasma levels at the end of surgery compared with no-AKI patients, and CFH correlated with serum creatinine at 48 h. Moreover, CFH levels inversely correlated with haptoglobin levels, which were significantly reduced at the end of surgery in LuTx patients with AKI. Because multiple other factors can contribute to AKI development in the complex clinical setting of LuTx, we next investigated the role of exogenous CFH administration in a mouse model of mild bilateral renal ischemia reperfusion injury (IRI). Exogenous administration of CFH after reperfusion caused overt AKI with creatinine increase, tubular injury, and enhanced markers of renal inflammation compared with vehicle-treated animals. In conclusion, CFH is a possible factor contributing to postoperative AKI after LuTx and promotes AKI in an experimental model of mild transient renal ischemia. Targeting CFH might be a therapeutic option to prevent AKI after LuTx. Full article
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14 pages, 2795 KiB  
Article
Different Acute Kidney Injury Patterns after Renal Ischemia Reperfusion Injury and Extracorporeal Membrane Oxygenation in Mice
by Robert Greite, Johanna Störmer, Faikah Gueler, Rasul Khalikov, Axel Haverich, Christian Kühn, Nodir Madrahimov and Ruslan Natanov
Int. J. Mol. Sci. 2022, 23(19), 11000; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911000 - 20 Sep 2022
Cited by 3 | Viewed by 1537
Abstract
The use of extracorporeal membrane oxygenation (ECMO) is associated with acute kidney injury (AKI) in thoracic organ transplantation. However, multiple other factors contribute to AKI development after these procedures such as renal ischemia-reperfusion injury (IRI) due to hypo-perfusion of the kidney during surgery. [...] Read more.
The use of extracorporeal membrane oxygenation (ECMO) is associated with acute kidney injury (AKI) in thoracic organ transplantation. However, multiple other factors contribute to AKI development after these procedures such as renal ischemia-reperfusion injury (IRI) due to hypo-perfusion of the kidney during surgery. In this study, we aimed to explore the kidney injury patterns in mouse models of ECMO and renal IRI. Kidneys of C57BL/6 mice were examined after moderate (35 min) and severe (45 min) unilateral transient renal pedicle clamping and 2 h of veno-venous ECMO. Renal injury markers, neutrophil infiltration, tubular transport function, pro-inflammatory cytokines, and renal heme oxygenase-1 (HO-1) expression were determined by immunofluorescence and qPCR. Both procedures caused AKI, but with different injury patterns. Severe neutrophil infiltration of the kidney was evident after renal IRI, but not following ECMO. Tubular transport function was severely impaired after renal IRI, but preserved in the ECMO group. Both procedures caused upregulation of pro-inflammatory cytokines in the renal tissue, but with different time kinetics. After ECMO, but not IRI, HO-1 was strongly induced in tubular cells indicating contact with hemolysis-derived proteins. After IRI, HO-1 was expressed on infiltrating myeloid cells in the tubulo-interstitial space. In conclusion, renal IRI and ECMO both caused AKI, but kidney damage after renal IRI was more pronounced including severe neutrophil infiltration and tubular transport impairment. Enhanced HO-1 expression in tubular cells after ECMO encourages limitation of hemolysis as a therapeutic approach to reduce ECMO-associated AKI. Full article
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19 pages, 4492 KiB  
Article
Hypothermia Alleviates Reductive Stress, a Root Cause of Ischemia Reperfusion Injury
by Kattri-Liis Eskla, Hans Vellama, Liisi Tarve, Hillar Eichelmann, Toomas Jagomäe, Rando Porosk, Vello Oja, Heikko Rämma, Nadežda Peet, Agu Laisk, Vallo Volke, Eero Vasar and Hendrik Luuk
Int. J. Mol. Sci. 2022, 23(17), 10108; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231710108 - 03 Sep 2022
Cited by 3 | Viewed by 1922
Abstract
Ischemia reperfusion injury is common in transplantation. Previous studies have shown that cooling can protect against hypoxic injury. To date, the protective effects of hypothermia have been largely associated with metabolic suppression. Since kidney transplantation is one of the most common organ transplant [...] Read more.
Ischemia reperfusion injury is common in transplantation. Previous studies have shown that cooling can protect against hypoxic injury. To date, the protective effects of hypothermia have been largely associated with metabolic suppression. Since kidney transplantation is one of the most common organ transplant surgeries, we used human-derived renal proximal tubular cells (HKC8 cell line) as a model of normal renal cells. We performed a temperature titration curve from 37 °C to 22 °C and evaluated cellular respiration and molecular mechanisms that can counteract the build-up of reducing equivalents in hypoxic conditions. We show that the protective effects of hypothermia are likely to stem both from metabolic suppression (inhibitory component) and augmentation of stress tolerance (activating component), with the highest overlap between activating and suppressing mechanisms emerging in the window of mild hypothermia (32 °C). Hypothermia decreased hypoxia-induced rise in the extracellular lactate:pyruvate ratio, increased ATP/ADP ratio and mitochondrial content, normalized lipid content, and improved the recovery of respiration after anoxia. Importantly, it was observed that in contrast to mild hypothermia, moderate and deep hypothermia interfere with HIF1 (hypoxia inducible factor 1)-dependent HRE (hypoxia response element) induction in hypoxia. This work also demonstrates that hypothermia alleviates reductive stress, a conceptually novel and largely overlooked phenomenon at the root of ischemia reperfusion injury. Full article
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11 pages, 924 KiB  
Article
Systemic and Renal Dynamics of Free Sulfhydryl Groups during Living Donor Kidney Transplantation
by Nora A. Spraakman, Annemieke M. Coester, Arno R. Bourgonje, Vincent B. Nieuwenhuijs, Jan-Stephan F. Sanders, Henri G. D. Leuvenink, Harry van Goor and Gertrude J. Nieuwenhuijs-Moeke
Int. J. Mol. Sci. 2022, 23(17), 9789; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179789 - 29 Aug 2022
Cited by 2 | Viewed by 1135
Abstract
During ischemia–reperfusion injury (IRI), reactive oxygen species are produced that can be scavenged by free sulfhydryl groups (R-SH, free thiols). In this study, we hypothesized that R-SH levels decrease as a consequence of renal IRI and that R-SH levels reflect post-transplant graft function. [...] Read more.
During ischemia–reperfusion injury (IRI), reactive oxygen species are produced that can be scavenged by free sulfhydryl groups (R-SH, free thiols). In this study, we hypothesized that R-SH levels decrease as a consequence of renal IRI and that R-SH levels reflect post-transplant graft function. Systemic venous, arterial, renal venous, and urinary samples were collected in donors and recipients before, during, and after transplantation. R-SH was measured colorimetrically. Systemic arterial R-SH levels in recipients increased significantly up to 30 sec after reperfusion (p < 0.001). In contrast, renal venous R-SH levels significantly decreased at 5 and 10 min compared to 30 sec after reperfusion (both p < 0.001). This resulted in a significant decrease in delta R-SH (defined as the difference between renal venous and systemic arterial R-SH levels) till 30 sec after reperfusion (p < 0.001), indicating a net decrease in R-SH levels across the transplanted kidney. Overall, these results suggest trans-renal oxidative stress as a consequence of IRI during kidney transplantation, reflected by systemic and renal changes in R-SH levels in transplant recipients. Full article
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17 pages, 3275 KiB  
Article
The Benefits of Fibrinolysis Combined with Venous Systemic Oxygen Persufflation (VSOP) in a Rat Model of Donation after Circulatory Death and Orthotopic Liver Transplantation
by Nadja Kröger, Zoltan Czigany, Jipin Jiang, Mamdouh Afify, Pascal Paschenda, Kazuyuki Nagai, Shintaro Yagi and René H. Tolba
Int. J. Mol. Sci. 2022, 23(9), 5272; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23095272 - 09 May 2022
Cited by 1 | Viewed by 1458
Abstract
Organ shortage has led to the increasing utilization of livers retrieved from donors after circulatory death (DCD). These pre-damaged organs are susceptible to further warm ischemia and exhibit minimal tolerance for cold storage. The aim was thus to examine the effects of fibrinolysis [...] Read more.
Organ shortage has led to the increasing utilization of livers retrieved from donors after circulatory death (DCD). These pre-damaged organs are susceptible to further warm ischemia and exhibit minimal tolerance for cold storage. The aim was thus to examine the effects of fibrinolysis combined with Venous Systemic Oxygen Persufflation (VSOP) on the preservation of DCD livers in vivo. Livers of male Lewis rats were explanted after 45 min of warm ischemia, cold-stored for 18 h, and transplanted into a recipient animal. Livers were left untreated or underwent either VSOP or fibrinolysis via Streptokinase (SK) or received combined SK and VSOP. Combined treatment exhibited improved microvascular flow at 168 h (p = 0.0009) and elevated microperfusion velocity at 24 h post-transplantation (p = 0.0007). Combination treatment demonstrated increased portal venous flow (PVF) at 3 and 24 h post-transplantation (p = 0.0004, p < 0.0001), although SK and VSOP analogously achieved increases at 24 h (p = 0.0036, p = 0.0051). Enzyme release was decreased for combination treatment (p = 0.0002, p = 0.0223) and lactate dehydrogenase (LDH) measurements were lower at 24 h post-transplantation (p = 0.0287). Further supporting findings have been obtained in terms of serum cytokine levels and in the alterations of endothelial injury markers. The combination treatment of SK + VSOP might provide improved organ integrity and viability and may therefore warrant further investigation as a potential therapeutic approach in the clinical setting of DCD. Full article
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Review

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14 pages, 1238 KiB  
Review
Molecular Markers of Kidney Transplantation Outcome: Current Omics Tools and Future Developments
by Maryne Lepoittevin, Thomas Kerforne, Luc Pellerin, Thierry Hauet and Raphael Thuillier
Int. J. Mol. Sci. 2022, 23(11), 6318; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23116318 - 05 Jun 2022
Cited by 5 | Viewed by 2087
Abstract
Purpose of review: The emerging field of molecular predictive medicine is aiming to change the traditional medical approach in renal transplantation. Many studies have explored potential biomarker molecules with predictive properties in renal transplantation, issued from omics research. Herein, we review the biomarker [...] Read more.
Purpose of review: The emerging field of molecular predictive medicine is aiming to change the traditional medical approach in renal transplantation. Many studies have explored potential biomarker molecules with predictive properties in renal transplantation, issued from omics research. Herein, we review the biomarker molecules of four technologies (i.e., Genomics, Transcriptomics, Proteomics, and Metabolomics) associated with favorable kidney transplant outcomes. Recent findings: Several panels of molecules have been associated with the outcome that the majority of markers are related to inflammation and immune response; although. other molecular ontologies are also represented, such as proteasome, growth, regeneration, and drug metabolism. Throughout this review, we highlight the lack of properly validated statistical demonstration. Indeed, the most preeminent molecular panels either remain at the limited size study stage or are not confirmed during large-scale studies. At the core of this problem, we identify the methodological shortcomings and propose a comprehensive workflow for discovery and validation of molecular biomarkers that aims to improve the relevance of these tools in the future. Summary: Overall, adopting a patient management through omics approach could bring remarkable improvement to transplantation success. An increased effort and investment between scientists, medical biologists, and clinicians seem to be the path toward a proper solution. Full article
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19 pages, 2003 KiB  
Review
Preservation of Organs to Be Transplanted: An Essential Step in the Transplant Process
by Maryne Lepoittevin, Sébastien Giraud, Thomas Kerforne, Benoit Barrou, Lionel Badet, Petru Bucur, Ephrem Salamé, Claire Goumard, Eric Savier, Julien Branchereau, Pascal Battistella, Olaf Mercier, Sacha Mussot, Thierry Hauet and Raphael Thuillier
Int. J. Mol. Sci. 2022, 23(9), 4989; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094989 - 30 Apr 2022
Cited by 8 | Viewed by 3341
Abstract
Organ transplantation remains the treatment of last resort in case of failure of a vital organ (lung, liver, heart, intestine) or non-vital organ (essentially the kidney and pancreas) for which supplementary treatments exist. It remains the best alternative both in terms of quality-of-life [...] Read more.
Organ transplantation remains the treatment of last resort in case of failure of a vital organ (lung, liver, heart, intestine) or non-vital organ (essentially the kidney and pancreas) for which supplementary treatments exist. It remains the best alternative both in terms of quality-of-life and life expectancy for patients and of public health expenditure. Unfortunately, organ shortage remains a widespread issue, as on average only about 25% of patients waiting for an organ are transplanted each year. This situation has led to the consideration of recent donor populations (deceased by brain death with extended criteria or deceased after circulatory arrest). These organs are sensitive to the conditions of conservation during the ischemia phase, which have an impact on the graft’s short- and long-term fate. This evolution necessitates a more adapted management of organ donation and the optimization of preservation conditions. In this general review, the different aspects of preservation will be considered. Initially done by hypothermia with the help of specific solutions, preservation is evolving with oxygenated perfusion, in hypothermia or normothermia, aiming at maintaining tissue metabolism. Preservation time is also becoming a unique evaluation window to predict organ quality, allowing repair and/or optimization of recipient choice. Full article
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