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1. Preventing acute kidney injury during transplantation: the application of novel oxygen carriers

Author

Franck Zal, Benoit Barrou, Jacques Kaminski, David Soussi, Lionel Badet, Eric Delpy, Jérôme Danion, Xavier Matillon, Abdelsalam Kasil, Yse Sauvageon, Gianluca Donatini, Raphael Thuillier, Thierry Hauet, Xavier Rod, Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers, Centre hospitalier universitaire de Poitiers (CHU Poitiers), HEMARINA SA, U1082, Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Institut National de la Recherche Agronomique (INRA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Faculté de Médecine et de Pharmacie, Université officielle de Bukavu, and Service de chirurgie viscérale et endocrinienne

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Delayed Graft Function, 03 medical and health sciences, 0302 clinical medicine, Hypothermia, Induced, medicine, ischemia reperfusion, Animals, Humans, Pharmacology (medical), Oxygen carrier, Kidney transplantation, Pharmacology, Machine perfusion, business.industry, machine perfusion, Acute kidney injury, Endothelial Cells, General Medicine, Acute Kidney Injury, Hypothermia, medicine.disease, Kidney Transplantation, Tissue Donors, 3. Good health, Oxygen, Transplantation, surgical procedures, operative, 030104 developmental biology, 030220 oncology & carcinogenesis, Anesthesia, medicine.symptom, organ preservation, business, transplantation
Abstract

International audience; Introduction: Delayed graft function (DGF) has a significant impact on kidney transplantation outcome. One of the underlying pivotal mechanisms is organ preservation and associated hypothermia and biochemical alteration. Area covered: This paper focuses on organ preservation and its clinical consequences and describes 1. A comprehensive presentation of the pathophysiological mechanism involved in delayed graft function development; 2. The impact on endothelial cells and microvasculature integrity and the consequences on transplanted organ outcome; 3. The reassessment of dynamic organ preservation motivated by the growing use of extended criteria donors and the interest in the potential of normothermia; 4. The role of oxygenation during dynamic preservation; and 5. Novel oxygen carriers and their proof of concept in transplantation, among which M101 (HEMO(2)life (R)) is currently the most extensively investigated. Expert opinion: Metabolic disturbances and imbalance of oxygen supply during preservation highlight the importance of providing oxygen. Normothermia, permitted by recent advances in machine perfusion technology, appears to be the leading edge of preservation technology. Several oxygen transporters are compatible with normothermia; however, only M101 also demonstrates compatibility with standard hypothermic preservation.

Published
2019
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2. Impact of hypothermia and oxygen deprivation on the cytoskeleton in organ preservation models

Author

Raphael Thuillier, Thierry Hauet, Service de Biochimie, Fédération Hospitalo-universitaire SUrvival oPtimization in ORgan Transplantation (FHU SUPORT), Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours-Université de Tours, Faculté de Médecine et de Pharmacie, Université officielle de Bukavu, Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers, Génétique, Expérimentation et Système Innovants (GenESI), Institut National de la Recherche Agronomique (INRA), Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours (UT)-Université de Tours (UT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), ProdInra, Migration, Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours (UT)-Université de Tours (UT)-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), and Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Article Subject, anoxie, lcsh:R, transplantation d'organe, lcsh:Medicine, cytoskeleton, Hypothermia, Organ Preservation, Microtubules, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Oxygen, Actin Cytoskeleton, ischémie reperfusion, Humans, Urology and Nephrology, hypothermie, Research Article, Urologie et Néphrologie
Abstract

International audience; Ischemia reperfusion (IR) lesions are an unavoidable consequence of organ transplantation. Researching new therapeutics against these lesions requires the definition of early mechanisms. The cytoskeleton is composed of 3 types of filaments: microfilaments, intermediate filaments, and microtubules. We aimed to characterize the influence of preservation on their phenotype. In an in vitro model using primary human endothelial cells reproducing the conditions of organ preservation, two aspects were explored: (a) the impact of IR and cold ischemia time on each filament type, evaluating the roles of temperature, solution, and oxygen; and (b) the potential of cytoskeleton-mediated therapy to alleviate cell death. Results showed that intermediary filaments were unaffected, while microfilaments showed radical changes with disappearance of the structure replaced by a disorganized array of nodules; moreover, microtubules almost completely disappeared with time. Furthermore, temperature, and not oxygen deprivation or the solution, was the determining factor of the cytoskeleton's loss of integrity during preservation. Finally, pharmaceutical intervention could indeed preserve fiber structure but did not alter survival. Our work shows that improvement of preservation must include a more adapted temperature before considering oxygen, as it could profoundly improve cytoskeleton organization and thus cell fate. This highlights the importance of this structure for the development of new therapeutics and the definition of graft quality biomarkers.

Published
2018
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3. Protecting the mitochondria against ischemia reperfusion: A gassy solution?

Author

Thierry Hauet, Raphael Thuillier, Université de Poitiers - Faculté de Médecine et de Pharmacie, Université de Poitiers, Fédération Hospitalo-universitaire SUrvival oPtimization in ORgan Transplantation (FHU SUPORT), Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours-Université de Tours, Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), UE1372 GENESI, IBiSA Plateforme MOPICT, Institut National de la Recherche Agronomique (INRA), Service de Biochimie, Faculté de Médecine et de Pharmacie, Université officielle de Bukavu, Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Cellules Dendritiques, Immunomodulation et Greffes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers, Génétique, Expérimentation et Système Innovants (GenESI), CHU Limoges-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), and Université de Tours (UT)-Université de Tours (UT)

Subjects
0301 basic medicine, medicine.medical_specialty, Ischemia, Delayed Graft Function, 030230 surgery, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Organ transplantation, 03 medical and health sciences, 0302 clinical medicine, ischémie reperfusion, Immunology and Allergy, Medicine, Humans, Pharmacology (medical), Hydrogen Sulfide, cardiovascular diseases, Intensive care medicine, Kidney transplantation, Transplantation, business.industry, transplantation d'organe, medicine.disease, reperfusion injury, Kidney Transplantation, 3. Good health, Surgery, mitochondria, 030104 developmental biology, mitochondrie, business, Reperfusion injury, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Organ transplantation success has seen great improvements in past decades due to progresses in immune-suppressive regiments. However, lack of long-term graft outcome improvement, added to increased marginal donors use, has recently shifted the focus towards the peri-transplant period and particularly ischemia reperfusion injury (IRI). The recent acknowledgment of the link between IRI and outcome, short or long term, has rekindled interest in the study of the physiopathology associated with organ preservation and the methods to optimize it. This article is protected by copyright. All rights reserved.

Published
2017
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4. A new approach in organ preservation: potential role of new polymers

Author

Thierry Hauet, Michel Eugene, Ischémie - Reperfusion en transplatation rénale, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers, Génétique Expérimentale en Productions Animales (GEPA), Institut National de la Recherche Agronomique (INRA), Faculté de Médecine et de Pharmacie, Université officielle de Bukavu, and Centre hospitalier universitaire de Poitiers (CHU Poitiers)

Subjects
[SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Nephrology, medicine.medical_specialty, Polymers, Organ Preservation Solutions, 030232 urology & nephrology, Ischemia, Delayed Graft Function, Cold storage, polyethylene glycols, Context (language use), [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, 030230 surgery, Bioinformatics, Organ transplantation, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, Internal medicine, ischemia reperfusion, Humans, Medicine, immunocamouflage, Cryopreservation, business.industry, organ transplantation, Organ Preservation, Hypothermia, medicine.disease, Kidney Transplantation, 3. Good health, Surgery, Transplantation, medicine.symptom, business
Abstract

International audience; The storage conditions of the donor kidney may influence the deleterious consequences of ischemia/reperfusion (IR), which remains a major source of complications in clinical practice. Delayed graft function (DGF), seen in 20% to 50% of transplanted cadaver kidneys, is a major risk factor affecting early and long-term graft survival, patient management, and costs of transplantation. Cold preservation plays a key role in this process and is based on hypothermia and high potassium solutions. In this review, the authors focused on the major molecular mechanisms of cold storage (CS) injury at the cellular level, which have been recently evidenced with modern biochemical and cell biologic methods. These newly uncovered aspects of cold preservation injury are often not fully addressed by preservation solutions in current clinical practice. The role of new molecules such as polyethylene glycol (PEG) is presented and their properties are analyzed in the organ preservation context. PEG improves organ function recovery and reduces inflammation and fibrosis development in several models. Because organs shortage is also a real public health problem, organs from non-heart beating donors or marginal donors are now used to expand pool of organs. As a consequence, the development of better organ preservation methods remains a major target and deserves scientific consideration.

Published
2008
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5. Strategies to optimize kidney recovery and preservation in transplantation: specific aspects in pediatric transplantation

Author

Thomas Kerforne, Sylvain Le Pape, Michel Pinsard, Tackwa Khalifeh, Edouard Baulier, S Maiga, Remy Coudroy, Frédéric Favreau, Thierry Hauet, Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université de Poitiers - Faculté de Médecine et de Pharmacie, Université de Poitiers, Faculté de Médecine et de Pharmacie, and Université officielle de Bukavu

Subjects
Nephrology, medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Ischemia, Bioinformatics, Pediatrics, Cell therapy, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Child, Kidney transplantation, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Kidney, business.industry, Mesenchymal stem cell, Organ Preservation, Stem-cell therapy, medicine.disease, Kidney Transplantation, Tissue Donors, 3. Good health, Transplantation, medicine.anatomical_structure, Pediatrics, Perinatology and Child Health, Immunology, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

In renal transplantation, live donor kidney grafts are associated with optimum success rates due to the shorter period of ischemia during the surgical procedure. The current shortage of donor organs for adult patients has caused a shift towards deceased donors, often with co-morbidity factors, whose organs are more sensitive to ischemia-reperfusion injury, which is unavoidable during transplantation. Donor management is pivotal to kidney graft survival through the control of the ischemia-reperfusion sequence, which is known to stimulate numerous deleterious or regenerative pathways. Although the key role of endothelial cells has been established, the complexity of the injury, associated with stimulation of different cell signaling pathways, such as unfolded protein response and cell death, prevents the definition of a unique therapeutic target. Preclinical transplant models in large animals are necessary to establish relationships and kinetics and have already contributed to the improvement of organ preservation. Therapeutic strategies using mesenchymal stem cells to induce allograft tolerance are promising advances in the treatment of the pediatric recipient in terms of reducing/withdrawing immunosuppressive therapy. In this review we focus on the different donor management strategies in kidney graft conditioning and on graft preservation consequences by highlighting the role of endothelial cells. We also propose strategies for preventing ischemia-reperfusion, such as cell therapy.

Published
2015
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6. Thrombin inhibition during kidney ischemia-reperfusion reduces chronic graft inflammation and tubular atrophy

Author

Laurent Macchi, Serge Milin, Thierry Hauet, Frédéric Favreau, O. Celhay, Raphael Thuillier, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Faculté de Médecine et de Pharmacie, Université officielle de Bukavu, Ischémie - Reperfusion en transplatation rénale, Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut National de la Recherche Agronomique (INRA), Conseil General de la Vienne, Region Poitou Charentes, Banque Tarneaud, Poitiers, CHU Poitiers Inserm, Societe Francophone de Transplantation, French Foundation of Transplantation, and Astra Zeneca

Subjects
Male, Pathology, P-selectin, CHRONIC ALLOGRAFT NEPHROPATHY, RENAL INJURY, Swine, [SDV]Life Sciences [q-bio], TO-MESENCHYMAL TRANSITION, 030232 urology & nephrology, Kidney, Tubular atrophy, ACTIVATION, 0302 clinical medicine, Medicine, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, Thrombin, Tissue Donors, 3. Good health, Proteinuria, medicine.anatomical_structure, Kidney Tubules, Creatinine, Reperfusion Injury, HEART, medicine.symptom, medicine.medical_specialty, Ischemia-reperfusion injury, Inflammation, Transplantation, Autologous, Antithrombins, MECHANISMS, 03 medical and health sciences, Cadaver, Animals, Humans, Viaspan, RNA, Messenger, MODULATION, 030304 developmental biology, DNA Primers, Transplantation, Renal ischemia, business.industry, TRIMETAZIDINE, medicine.disease, Kidney Transplantation, Postmortem Changes, CELLS, business, Reperfusion injury, Kidney disease
Abstract

International audience; Background. Ischemia-reperfusion injury (IRI) is an unavoidable component of transplantation and correlates with delayed graft function, acute rejection, chronic fibrosis, and graft loss. Currently, new donor pools are considered to alleviate pressure on waiting lists, such as deceased after cardiac death donors (DCD) and extended criteria donors. Because these organs are particularly sensitive to IRI, there is a need for novel preservation paradigms. We assessed the effect of anticoagulation therapy during graft preservation on IRI and graft outcome. Methods. In a large white autotransplanted pig model, kidneys underwent warm ischemia for 60 min, mimicking DCD, then were preserved for 24 hr at 4 degrees C, in University of Wisconsin solution. Animals were followed up 3 months, functional, histologic, and molecular parameters were assessed. In treated groups, antithrombin was added to collection and preservation protocols. Results. Treatment improved chronic graft function, reduced tubular atrophy, and substantially increased animal survival. Quantitative polymerase chain reaction analysis determined that markers of inflammation, such as interferon-gamma, tumor necrosis factor-alpha, interleukin (IL)-2, -1Rn, and -10, were significantly reduced in treated grafts. Histologic analysis revealed a lowering of CD3+ invasion. P selectin and C3 mRNA expressions were reduced in treated groups, indicative of lowered complement production and endothelial cell activation. Vascular endothelium growth factor protein expression was up-regulated, suggesting vascular network remodeling. Conclusion. Inhibition of thrombin during preservation of DCD graft preserved renal integrity and function, protecting against chronic inflammation and tissue damage. Thus, coagulation seems to be a critical target for the development of therapeutic strategies to improve kidney quality for transplantation.

Published
2010
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7. Anti-thrombin therapy during warm ischemia and cold preservation prevents chronic kidney graft fibrosis in a DCD model

Author

Thierry Hauet, Xiangyang Zhu, R. Thuillier, S. Milin, Frédéric Favreau, Lilach O. Lerman, Gérard Mauco, Emilie Manguy, Jerome Cau, Ischémie - Reperfusion en transplatation rénale, Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine et de Pharmacie, Université officielle de Bukavu, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Division of Nephrology and Hypertension, Mayo Clinic, Génétique Expérimentale en Productions Animales (GEPA), Institut National de la Recherche Agronomique (INRA), ProdInra, Migration, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers

Subjects
Male, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Benzylamines, Pathology, Adenosine, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, Swine, 030232 urology & nephrology, 030230 surgery, Kidney, Peritubular capillaries, chemistry.chemical_compound, 0302 clinical medicine, Transforming Growth Factor beta, Fibrosis, Insulin, Immunology and Allergy, Pharmacology (medical), direct thrombin inhibitor, ischemia reperfusion injury, [SDV.SA] Life Sciences [q-bio]/Agricultural sciences, Temperature, Organ Preservation, Glutathione, Tissue Donors, 3. Good health, medicine.anatomical_structure, Tissue Plasminogen Activator, Models, Animal, Signal Transduction, kidney preservation, medicine.medical_specialty, Allopurinol, Organ Preservation Solutions, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Transplantation, Autologous, Article, 03 medical and health sciences, Raffinose, interstitial fibrosis/tubular atrophy, Plasminogen Activator Inhibitor 1, medicine, Renal fibrosis, Animals, Humans, RNA, Messenger, Sirius Red, DNA Primers, Transplantation, Base Sequence, business.industry, graft function, Anticoagulants, Kidney metabolism, medicine.disease, Kidney Transplantation, CTGF, Oxidative Stress, chemistry, Chronic Disease, Azetidines, business, Reperfusion injury
Abstract

International audience; Ischemia reperfusion injury (IRI) is pivotal for renal fibrosis development via peritubular capillaries injury. Coagulation represents a key mechanism involved in this process. Melagatran (R) (M), a thrombin inhibitor, was evaluated in an autotransplanted kidney model, using Large White pigs. To mimic deceased after cardiac death donor conditions, kidneys underwent warm ischemia (WI) for 60 min before cold preservation for 24 h in University of Wisconsin solution. Treatment with M before WI and/or in the preservation solution drastically improved survival at 3 months, reduced renal dysfunction related to a critical reduction in interstitial fibrosis, measured by Sirius Red staining. Tissue analysis revealed reduced expression of transforming growth factor-beta (TGF-beta) and activation level of its effectors phospho-Smad3, Smad4 and connective tissue growth factor (CTGF) after M treatment. Fibrinolysis activation was also observed, evidenced by downregulation of PAI-1 protein and gene expression. In addition, M reduced S100A4 expression and vimentin staining, which are markers for epithelial mesenchymal transition, a major pathway to chronic kidney fibrosis. Finally, expression of oxidative stress markers Nox2 and iNOS was reduced. We conclude that inhibition of thrombin is an effective therapy against IRI that reduces chronic graft fibrosis, with a significantly positive effect on survival.

Published
2010
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