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1.
Blood ; 143(8): 721-733, 2024 Feb 22.
Article in English | MEDLINE | ID: mdl-38048591

ABSTRACT

ABSTRACT: The volume of oxygen drawn from systemic capillaries down a partial pressure gradient is determined by the oxygen content of red blood cells (RBCs) and their oxygen-unloading kinetics, although the latter is assumed to be rapid and, therefore, not a meaningful factor. Under this paradigm, oxygen transfer to tissues is perfusion-limited. Consequently, clinical treatments to optimize oxygen delivery aim at improving blood flow and arterial oxygen content, rather than RBC oxygen handling. Although the oxygen-carrying capacity of blood is increased with transfusion, studies have shown that stored blood undergoes kinetic attrition of oxygen release, which may compromise overall oxygen delivery to tissues by causing transport to become diffusion-limited. We sought evidence for diffusion-limited oxygen release in viable human kidneys, normothermically perfused with stored blood. In a cohort of kidneys that went on to be transplanted, renal respiration correlated inversely with the time-constant of oxygen unloading from RBCs used for perfusion. Furthermore, the renal respiratory rate did not correlate with arterial O2 delivery unless this factored the rate of oxygen-release from RBCs, as expected from diffusion-limited transport. To test for a rescue effect, perfusion of kidneys deemed unsuitable for transplantation was alternated between stored and rejuvenated RBCs of the same donation. This experiment controlled oxygen-unloading, without intervening ischemia, holding all non-RBC parameters constant. Rejuvenated oxygen-unloading kinetics improved the kidney's oxygen diffusion capacity and increased cortical oxygen partial pressure by 60%. Thus, oxygen delivery to tissues can become diffusion-limited during perfusion with stored blood, which has implications in scenarios, such as ex vivo organ perfusion, major hemorrhage, and pediatric transfusion. This trial was registered at www.clinicaltrials.gov as #ISRCTN13292277.


Subject(s)
Erythrocytes , Oxygen , Humans , Child , Kidney
2.
Transpl Int ; 37: 12380, 2024.
Article in English | MEDLINE | ID: mdl-38463463

ABSTRACT

Donor organ biomarkers with sufficient predictive value in liver transplantation (LT) are lacking. We herein evaluate liver viability and mitochondrial bioenergetics for their predictive capacity towards the outcome in LT. We enrolled 43 consecutive patients undergoing LT. Liver biopsy samples taken upon arrival after static cold storage were assessed by histology, real-time confocal imaging analysis (RTCA), and high-resolution respirometry (HRR) for mitochondrial respiration of tissue homogenates. Early allograft dysfunction (EAD) served as primary endpoint. HRR data were analysed with a focus on the efficacy of ATP production or P-L control efficiency, calculated as 1-L/P from the capacity of oxidative phosphorylation P and non-phosphorylating respiration L. Twenty-two recipients experienced EAD. Pre-transplant histology was not predictive of EAD. The mean RTCA score was significantly lower in the EAD cohort (-0.75 ± 2.27) compared to the IF cohort (0.70 ± 2.08; p = 0.01), indicating decreased cell viability. P-L control efficiency was predictive of EAD (0.76 ± 0.06 in IF vs. 0.70 ± 0.08 in EAD-livers; p = 0.02) and correlated with the RTCA score. Both RTCA and P-L control efficiency in biopsy samples taken during cold storage have predictive capacity towards the outcome in LT. Therefore, RTCA and HRR should be considered for risk stratification, viability assessment, and bioenergetic testing in liver transplantation.


Subject(s)
Liver Transplantation , Primary Graft Dysfunction , Humans , Liver Transplantation/adverse effects , Graft Survival , Risk Factors , Liver/pathology , Energy Metabolism , Allografts/pathology , Primary Graft Dysfunction/etiology
3.
Nature ; 557(7703): 50-56, 2018 05.
Article in English | MEDLINE | ID: mdl-29670285

ABSTRACT

Liver transplantation is a highly successful treatment, but is severely limited by the shortage in donor organs. However, many potential donor organs cannot be used; this is because sub-optimal livers do not tolerate conventional cold storage and there is no reliable way to assess organ viability preoperatively. Normothermic machine perfusion maintains the liver in a physiological state, avoids cooling and allows recovery and functional testing. Here we show that, in a randomized trial with 220 liver transplantations, compared to conventional static cold storage, normothermic preservation is associated with a 50% lower level of graft injury, measured by hepatocellular enzyme release, despite a 50% lower rate of organ discard and a 54% longer mean preservation time. There was no significant difference in bile duct complications, graft survival or survival of the patient. If translated to clinical practice, these results would have a major impact on liver transplant outcomes and waiting list mortality.


Subject(s)
Allografts/physiology , Liver Transplantation/methods , Liver/physiology , Organ Preservation/methods , Temperature , Tissue and Organ Harvesting/methods , Adolescent , Adult , Aged , Aged, 80 and over , Allografts/pathology , Allografts/physiopathology , Allografts/standards , Bile Ducts/pathology , Bile Ducts/physiology , Bile Ducts/physiopathology , Female , Graft Survival , Humans , Length of Stay , Liver/enzymology , Liver Transplantation/adverse effects , Male , Middle Aged , Organ Preservation/adverse effects , Perfusion , Survival Analysis , Tissue Donors/supply & distribution , Tissue and Organ Harvesting/adverse effects , Treatment Outcome , Waiting Lists , Young Adult
4.
Transpl Int ; 36: 11804, 2023.
Article in English | MEDLINE | ID: mdl-37901298

ABSTRACT

Normothermic machine perfusion (NMP) has reshaped organ preservation in recent years. In this preclinical study, prolonged normothermic perfusions of discarded human kidney grafts were performed in order to investigate perfusion dynamics and identify potential quality and assessment indicators. Five human discarded kidney grafts were perfused normothermically (37°C) for 48 h using the Kidney Assist device with a red-blood-cell based perfusate with urine recirculation. Perfusion dynamics, perfusate and urine composition as well as injury markers were measured and analyzed. Donor age ranged from 41 to 68 years. All but one kidney were from brain dead donors. Perfusions were performed successfully for 48 h with all discarded kidneys. Median arterial flow ranged from 405 to 841 mL/min. All kidneys excreted urine until the end of perfusion (median 0.43 mL/min at the end of perfusion). While sodium levels were consistently lower in urine compared to perfusate samples, this was only seen for chloride and potassium in kidney KTX 2. Lactate, AST, LDH as well as pro-inflammatory cytokines increased over time, especially in kidneys KTX 3 and 4. Ex vivo normothermic perfusion is able to identify patterns of perfusion, biological function, and changes in inflammatory markers in heterogenous discarded kidney grafts.


Subject(s)
Kidney Transplantation , Kidney , Humans , Adult , Middle Aged , Aged , Perfusion , Organ Preservation , Extracorporeal Circulation
5.
Transpl Int ; 36: 11062, 2023.
Article in English | MEDLINE | ID: mdl-36936441

ABSTRACT

A positive crossmatch (XM+) is considered a contraindication to solid abdominal organ transplantation except liver transplantation (LT). Conflicting reports exist regarding the effects of XM+ on post-transplant outcomes. The goal of this retrospective single-center analysis is to evaluate the influence of XM+ on relevant outcome parameters such as survival, graft rejection, biliary and arterial complications. Forty-nine adult patients undergoing LT with a XM+ between 2002 and 2017 were included. XM+ LT recipients were matched 1:2 with crossmatch negative (XM-) LT recipients based on the balance of risk (BAR) score. Patient and graft survival were compared using Kaplan-Meier survival analysis and the log-rank test. Comparative analysis of clinical outcomes in XM+ and XM- groups were conducted. Patient and graft survival were similar in XM+ and XM- patients. Rejection episodes did not differ either. Recipients with a strong XM+ were more likely to develop a PCR+ CMV infection. A XM+ was not associated with a higher incidence of biliary or arterial complications. Donor age, cold ischemia time, PCR+ CMV infection and a rejection episode were associated with the occurrence of ischemic type biliary lesions. A XM+ has no effects on patient and graft survival or other relevant outcome parameters following LT.


Subject(s)
Cytomegalovirus Infections , Kidney Transplantation , Liver Transplantation , Adult , Humans , Retrospective Studies , Histocompatibility Testing , Graft Survival , Graft Rejection/epidemiology
6.
Transpl Int ; 36: 11374, 2023.
Article in English | MEDLINE | ID: mdl-37547751

ABSTRACT

The advent of Machine Perfusion (MP) as a superior form of preservation and assessment for cold storage of both high-risk kidney's and the liver presents opportunities in the field of beta-cell replacement. It is yet unknown whether such techniques, when applied to the pancreas, can increase the pool of suitable donor organs as well as ameliorating the effects of ischemia incurred during the retrieval process. Recent experimental models of pancreatic MP appear promising. Applications of MP to the pancreas, needs refinement regarding perfusion protocols and organ viability assessment criteria. To address the "Role of pancreas machine perfusion to increase the donor pool for beta cell replacement," the European Society for Organ Transplantation (ESOT) assembled a dedicated working group comprising of experts to review literature pertaining to the role of MP as a method of improving donor pancreas quality as well as quantity available for transplant, and to develop guidelines founded on evidence-based reviews in experimental and clinical settings. These were subsequently refined during the Consensus Conference when this took place in Prague.


Subject(s)
Organ Preservation , Organ Transplantation , Humans , Organ Preservation/methods , Pancreas , Perfusion/methods , Tissue Donors
7.
Int J Mol Sci ; 24(11)2023 May 31.
Article in English | MEDLINE | ID: mdl-37298486

ABSTRACT

The majority of organs used for liver transplantation come from brain-dead donors (DBD). In order to overcome the organ shortage, increasingly donation after circulatory death (DCD) organs are also considered. Since normothermic machine perfusion (NMP) restores metabolic activity and allows for in-depth assessment of organ quality and function prior to transplantation, such organs may benefit from NMP. We herein compare the bioenergetic performance through a comprehensive evaluation of mitochondria by high-resolution respirometry in tissue biopsies and the inflammatory response in DBD and DCD livers during NMP. While livers were indistinguishable by perfusate biomarker assessment and histology, our findings revealed a greater impairment of mitochondrial function in DCD livers after static cold storage compared to DBD livers. During subsequent NMPs, DCD organs recovered and eventually showed a similar performance as DBD livers. Cytokine expression analysis showed no differences in the early phase of NMP, while towards the end of NMP, significantly elevated levels of IL-1ß, IL-5 and IL-6 were found in the perfusate of DCD livers. Based on our results, we find it worthwhile to reconsider more DCD organs for transplantation to further extend the donor pool. Therefore, donor organ quality criteria must be developed, which may include an assessment of bioenergetic function and cytokine quantification.


Subject(s)
Liver Transplantation , Tissue and Organ Procurement , Humans , Liver/pathology , Liver Transplantation/methods , Tissue Donors , Perfusion/methods , Energy Metabolism , Organ Preservation/methods
8.
Transpl Int ; 35: 10420, 2022.
Article in English | MEDLINE | ID: mdl-35711321

ABSTRACT

Donor kidney assessment may improve organ utilisation. Normothermic Machine Perfusion (NMP) has the potential to facilitate this advance. The mechanism of action is not yet determined and we aimed to assess mitochondrial function during NMP. Anaesthetised pigs (n = 6) had one kidney clamped for 60 min. The healthy contralateral kidney was removed and underwent NMP for 8 h (healthy control (HC), n = 6). Following 60 min warm ischaemia the injured kidney underwent HMP for 24 h, followed by NMP for 8 h (n = 6). Mitochondria were extracted from fresh tissue for analysis. Injured kidneys were analysed as two separate groups (IMa, n = 3 and IMb, n = 3). Renal resistance was higher (0.39ï, ± 0.29 vs. 1.65ï, ± 0.85; p = 0.01) and flow was lower (55ï, ± 28 vs. 7ï, ± 4; p = 0.03) during HMP in IMb than IMa. NMP blood flow was higher in IMa versus IMb (2-way ANOVA; p < 0.001) After 60 min NMP, O2 consumption was significantly lower in IMb versus IMa (p ≤ 0.002). State-3 respiration was significantly different between the groups (37ï, ± 19 vs. 24ï, ± 14 vs. 10ï, ± 8; nmolO2/min/mg; p = 0.049). Lactate levels were significantly lower in IMa versus IMb (p = 0.028). Mitochondrial respiration levels during NMP may be suggestive of kidney viability. Oxygen consumption, renal blood flow and lactate can differentiate severity of kidney injury during NMP.


Subject(s)
Kidney , Organ Preservation , Animals , Humans , Kidney/metabolism , Lactates/metabolism , Mitochondria , Oxygen Consumption , Perfusion , Swine , Tissue Survival
9.
Transpl Int ; 35: 10355, 2022.
Article in English | MEDLINE | ID: mdl-35651880

ABSTRACT

Normothermic machine perfusion (NMP) allows for ex vivo viability and functional assessment prior to liver transplantation (LT). Hyperspectral imaging represents a suitable, non-invasive method to evaluate tissue morphology and organ perfusion during NMP. Liver allografts were subjected to NMP prior to LT. Serial image acquisition of oxygen saturation levels (StO2), organ hemoglobin (THI), near-infrared perfusion (NIR) and tissue water indices (TWI) through hyperspectral imaging was performed during static cold storage, at 1h, 6h, 12h and at the end of NMP. The readouts were correlated with perfusate parameters at equivalent time points. Twenty-one deceased donor livers were included in the study. Seven (33.0%) were discarded due to poor organ function during NMP. StO2 (p < 0.001), THI (p < 0.001) and NIR (p = 0.002) significantly augmented, from static cold storage (pre-NMP) to NMP end, while TWI dropped (p = 0.005) during the observational period. At 12-24h, a significantly higher hemoglobin concentration (THI) in the superficial tissue layers was seen in discarded, compared to transplanted livers (p = 0.036). Lactate values at 12h NMP correlated negatively with NIR perfusion index between 12 and 24h NMP and with the delta NIR perfusion index between 1 and 24h (rs = -0.883, p = 0.008 for both). Furthermore, NIR and TWI correlated with lactate clearance and pH. This study provides first evidence of feasibility of hyperspectral imaging as a potentially helpful contact-free organ viability assessment tool during liver NMP.


Subject(s)
Hyperspectral Imaging , Organ Preservation , Hemoglobins , Humans , Lactates , Liver/diagnostic imaging , Organ Preservation/methods , Perfusion/methods , Pilot Projects
10.
Transpl Int ; 35: 10915, 2022.
Article in English | MEDLINE | ID: mdl-36406781

ABSTRACT

The European Society for Organ Transplantation (ESOT) has created a platform for the development of rigorous and regularly updated evidence based guidelines for clinical practice in the transplantation field. A dedicated Guideline Taskforce, including ESOT-council members, a representative from the Centre for Evidence in Transplantation, editors of the journal Transplant International has developed transparent procedures to guide the development of guidelines, recommendations, and consensus statements. During ESOT's first Consensus Conference in November 2022, leading experts will present in-depth evidence based reviews of nine themes and will propose recommendations aimed at reaching a consensus after public discussion and assessment by an independent jury. All recommendations and consensus statements produced for the nine selected topics will be published including the entire evidence-based consensus-finding process. An extensive literature review of each topic was conducted to provide final evidence and/or expert opinion.


Subject(s)
Organ Transplantation , Humans , Consensus , Societies, Medical
11.
Artif Organs ; 46(4): 710-714, 2022 Apr.
Article in English | MEDLINE | ID: mdl-35018641

ABSTRACT

Kidney transplantation is limited due to the organ scarcity and the large discrepancy between transplantable organs and patients on the waiting list. Ex-situ normothermic kidney preservation has been studied extensively as a tool to enlarge the donor pool and to enable viability assessment. Urine recirculation, for volume control, was applied to perfuse a discarded human kidney for 48 hours. Long-term kidney NMP was feasible under stable hemodynamic conditions with a physiological acid-base-balance and an intact histological morphology of the organ.


Subject(s)
Kidney Transplantation , Organ Preservation , Humans , Kidney , Perfusion , Tissue Donors
12.
Curr Opin Organ Transplant ; 27(5): 446-453, 2022 10 01.
Article in English | MEDLINE | ID: mdl-35857331

ABSTRACT

PURPOSE OF REVIEW: This review aims to summarize the latest original preclinical and clinical articles in the setting of normothermic machine perfusion (NMP) of kidney grafts. RECENT FINDINGS: Kidney NMP can be safely translated into the clinical routine and there is increasing evidence that NMP may be beneficial in graft preservation especially in marginal kidney grafts. Due to the near-physiological state during NMP, this technology may be used as an ex-vivo organ assessment and treatment platform. There are reports on the application of mesenchymal stromal/stem cells, multipotent adult progenitor cells and microRNA during kidney NMP, with first data indicating that these therapies indeed lead to a decrease in inflammatory response and kidney injury. Together with the demonstrated possibility of prolonged ex-vivo perfusion without significant graft damage, NMP could not only be used as a tool to perform preimplant graft assessment. Some evidence exists that it truly has the potential to be a platform to treat and repair injured kidney grafts, thereby significantly reducing the number of declined organs. SUMMARY: Kidney NMP is feasible and can potentially increase the donor pool not only by preimplant graft assessment, but also by ex-vivo graft treatment.


Subject(s)
Kidney Transplantation , Organ Preservation , Adult , Humans , Kidney , Kidney Transplantation/adverse effects , Organ Preservation/adverse effects , Perfusion , Tissue Donors
13.
Am J Transplant ; 21(5): 1740-1753, 2021 05.
Article in English | MEDLINE | ID: mdl-33021021

ABSTRACT

We describe a proteomics analysis to determine the molecular differences between normothermically perfused (normothermic machine perfusion, NMP) human kidneys with urine recirculation (URC) and urine replacement (UR). Proteins were extracted from 16 kidney biopsies with URC (n = 8 donors after brain death [DBD], n = 8 donors after circulatory death [DCD]) and three with UR (n = 2 DBD, n = 1 DCD), followed by quantitative analysis by mass spectrometry. Damage-associated molecular patterns (DAMPs) were decreased in kidney tissue after 6 hours NMP with URC, suggesting reduced inflammation. Vasoconstriction was also attenuated in kidneys with URC as angiotensinogen levels were reduced. Strikingly, kidneys became metabolically active during NMP, which could be enhanced and prolonged by URC. For instance, mitochondrial succinate dehydrogenase enzyme levels as well as carbonic anhydrase were enhanced with URC, contributing to pH stabilization. Levels of cytosolic and the mitochondrial phosphoenolpyruvate carboxykinase were elevated after 24 hours of NMP, more prevalent in DCD than DBD tissue. Key enzymes involved in glucose metabolism were also increased after 12 and 24 hours of NMP with URC, including mitochondrial malate dehydrogenase and glutamic-oxaloacetic transaminase, predominantly in DCD tissue. We conclude that NMP with URC permits prolonged preservation and revitalizes metabolism to possibly better cope with ischemia reperfusion injury in discarded kidneys.


Subject(s)
Organ Preservation , Proteomics , Homeostasis , Humans , Kidney , Perfusion
14.
Transpl Int ; 34(4): 657-668, 2021 04.
Article in English | MEDLINE | ID: mdl-33570795

ABSTRACT

With a later onset of diabetes complications and thus increasing age of transplant candidates, many centers have extended upper age limits for pancreas transplantation. This study investigates the effect of recipient and donor age on outcomes after pancreas transplantation.We retrospectively analyzed 565 pancreas transplants performed at two Eurotransplant centers. The cohort was split at a recipient and donor age of 50 and 40 years, respectively. Median recipient age in old patients (≥50 years; 27.2%) was 54 years and 40 years in young patients (<50 years). Compared to young recipients, old recipients had an inferior patient survival rate (≥50: 5yr, 82.8%; 10yr, 65.6%; <50: 5yr, 93.3%; 10yr, 82.0%; P < 0.0001). Old recipients demonstrated comparable death-censored pancreas (≥50: 1yr, 80.6%; 5yr, 70.2%; <50: 1yr, 87.3%; 5yr, 77.8%; P = 0.35) and kidney graft survival (≥50: 1yr, 97.4%; 5yr, 90.6%; <50: 1yr, 97.8%; 5yr, 90.2%; P = 0.53) compared to young recipients. Besides a lower rate of kidney rejection, similar relative risks for postoperative complications were detected in old and young patients. This study shows that despite an increased mortality in old recipients, excellent graft survival can be achieved similar to that of young patients. Age alone should not exclude patients from receiving a pancreas transplant.


Subject(s)
Kidney Transplantation , Pancreas Transplantation , Graft Rejection/epidemiology , Graft Survival , Humans , Middle Aged , Retrospective Studies , Tissue Donors , Treatment Outcome
15.
Pediatr Transplant ; 25(7): e14075, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34185384

ABSTRACT

BACKGROUND: Early biliary complications (EBC) constitute a burden after pediatric liver transplantation frequently requiring immediate therapy. We aimed to assess the impact of EBC on short- and long-term patient and graft survival as well as post-transplant morbidity. METHODS: We analyzed 121 pediatric liver transplantations performed between 1984 and 2019 at the Medical University of Innsbruck for the occurrence of early (<90 days) biliary complications and investigated the influence of EBC on patient and graft survival. RESULTS: Early biliary complications occurred in 30 (24.8%) out of the 121 pediatric liver transplant recipients. Patient survival at 15 years (89.2% vs. 84.2%, p = .65) and all-cause (82.5% vs. 74.0%) and death-censored graft survival (82.5% vs. 75.1%, p = .71) at 10 years were similar between the EBC and the non-EBC group. The EBC group had a significantly longer ICU (25 vs. 16 days, p < .001) and initial hospital stay (64 vs. 42 days, p = .002). Livers of patients with EBC were characterized by multiple bile ducts (33.3% vs. 13.2%, p = .027), and patients with EBC had a higher risk to develop late biliary complications (OR 2.821 [95% CI 1.049-7.587], p = .044) and bowel obstruction/perforation (OR 4.388 [95% CI 1.503-12.812], p = .007). CONCLUSION: Early biliary complications after pediatric liver transplantation is frequent. The occurrence of EBC significantly increased post-transplant morbidity without affecting mortality. Multiple bile ducts were the only risk factor for the development of EBC in our cohort.


Subject(s)
Biliary Tract Diseases/mortality , Graft Survival , Liver Transplantation , Postoperative Complications/mortality , Adolescent , Austria/epidemiology , Female , Humans , Male , Risk Factors , Survival Rate
16.
Int J Mol Sci ; 22(10)2021 May 15.
Article in English | MEDLINE | ID: mdl-34063399

ABSTRACT

Transplantation represents the treatment of choice for many end-stage diseases but is limited by the shortage of healthy donor organs. Ex situ normothermic machine perfusion (NMP) has the potential to extend the donor pool by facilitating the use of marginal quality organs such as those from donors after cardiac death (DCD) and extended criteria donors (ECD). NMP provides a platform for organ quality assessment but also offers the opportunity to treat and eventually regenerate organs during the perfusion process prior to transplantation. Due to their anti-inflammatory, immunomodulatory and regenerative capacity, mesenchymal stem cells (MSCs) are considered as an interesting tool in this model system. Only a limited number of studies have reported on the use of MSCs during ex situ machine perfusion so far with a focus on feasibility and safety aspects. At this point, no clinical benefits have been conclusively demonstrated, and studies with controlled transplantation set-ups are urgently warranted to elucidate favorable effects of MSCs in order to improve organs during ex situ machine perfusion.


Subject(s)
Mesenchymal Stem Cells , Organ Preservation/methods , Organ Transplantation/methods , Perfusion/methods , Animals , Humans , Mesenchymal Stem Cell Transplantation , Regenerative Medicine/methods , Time Factors , Tissue Donors , Tissue and Organ Procurement/methods
17.
Transpl Int ; 33(12): 1762-1778, 2020 12.
Article in English | MEDLINE | ID: mdl-32970891

ABSTRACT

Between 2000 and 2014, five patients received bilateral hand (n = 3), bilateral forearm (n = 1), and unilateral hand (n = 1) transplants at the Innsbruck Medical University Hospital. We provide a comprehensive report of the long-term results at 20 years. During the 6-20 years follow-up, 43 rejection episodes were recorded in total. Of these, 27.9% were antibody-related with serum donor-specific alloantibodies (DSA) and skin-infiltrating B-cells. The cell phenotype in rejecting skin biopsies changed and C4d-staining increased with time post-transplantation. In the long-term, a change in hand appearance was observed. The functional outcome was highly depending on the level of amputation. The number and severity of rejections did not correlate with hand function, but negatively impacted on the patients´ well-being and quality of life. Patient satisfaction significantly correlated with upper limb function. One hand allograft eventually developed severe allograft vasculopathy and was amputated at 7 years. The patient later died due to progressive gastric cancer. The other four patients are currently rejection-free with moderate levels of immunosuppression. Hand transplantation remains a therapeutic option for carefully selected patients. A stable immunologic situation with optimized and individually adopted immunosuppression favors good compliance and patient satisfaction and may prevent development of DSA.


Subject(s)
Graft Rejection , Hand Transplantation , Forearm , Humans , Quality of Life , Retrospective Studies
18.
Int J Mol Sci ; 21(9)2020 Apr 29.
Article in English | MEDLINE | ID: mdl-32365506

ABSTRACT

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.


Subject(s)
Mitochondria/metabolism , Oxidation-Reduction , Oxidative Stress , Reperfusion Injury/metabolism , Animals , Biomarkers , Humans , Liver/metabolism , Liver Transplantation/adverse effects , Organ Preservation/adverse effects , Organ Preservation/methods , Perfusion , Reactive Oxygen Species/metabolism , Reperfusion Injury/etiology , Reperfusion Injury/prevention & control
19.
Am J Transplant ; 19(1): 178-192, 2019 01.
Article in English | MEDLINE | ID: mdl-29758129

ABSTRACT

Transportable normothermic kidney perfusion for 24 hours or longer could enable viability assessment of marginal grafts, increased organ use, and improved transplant logistics. Eleven clinically declined kidneys were perfused normothermically, with 6 being from donors after brain death (median cold ischemia time 33 ± 36.9 hours) and 5 being from donors after circulatory death (36.2 ± 38.3 hours). Three kidneys were perfused using Ringer's lactate to replace excreted urine volume, and 8 kidneys were perfused using urine recirculation to maintain perfusate volume without fluid replenishment. In all cases, normothermic perfusion either maintained or slightly improved the histopathologically assessed tubular condition, and there was effective urine production in kidneys from both donors after brain death and donors after circulatory death (2367 ± 1798 mL vs 744.4 ± 198.4 mL, respectively; P = .44). Biomarkers, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 were successfully detected and quantified in the perfusate. All kidneys with urine recirculation were readily perfused for 24 hours (n = 8) and exhibited physiological perfusate sodium levels (140.7 ± 1.2 mmol/L), while kidneys without urine recirculation (n = 3) achieved a reduced normothermic perfusion time of 7.7 ± 1.5 hours and significantly higher perfusate sodium levels (159.6 ± 4.63 mmol/:, P < .01). Normothermic machine perfusion of human kidneys for 24 hours appears to be feasible, and urine recirculation was found to facilitate the maintenance of perfusate volume and homeostasis.


Subject(s)
Kidney Transplantation/methods , Kidney/surgery , Organ Preservation/methods , Perfusion , Urine , Aged , Biomarkers/urine , Cold Ischemia , Female , Glucose/analysis , Hemodynamics , Humans , Kidney Transplantation/instrumentation , Lactic Acid/analysis , Lipocalin-2/analysis , Male , Middle Aged , Organ Preservation/instrumentation
20.
Ann Surg ; 270(5): 915-922, 2019 11.
Article in English | MEDLINE | ID: mdl-31567358

ABSTRACT

OBJECTIVE: The aim of our prospective clinical trial was to test a tissue staining technique (real-time confocal analysis [RTCA]) as a rapid assessment tool for donor kidney quality and function in human kidney transplantation. SUMMARY BACKGROUND DATA: Tools for objective graft tissue viability assessment before kidney transplantation are lacking. RTCA has recently been established and tested in a pilot study using rodent kidneys. METHODS: RTCA was performed in kidney biopsies stained with SYTO16/PI and WGA. A score between -3 (100% nonviable) and +3 (100% viable) describes the sum of viable cells divided by the number of nonviable cells per examined area (glomerulus, proximal, and distal tubules). The primary study endpoint was the delayed graft function (DGF). RESULTS: Seventy-one kidney transplant recipients were transplanted. The median recipient and donor age were 58.5 and 57 years, respectively. Cold ischemia time was 13.6 ±â€Š4.7 hours; anastomosis time was 30.8 ±â€Š8.7 minutes (mean ±â€ŠSD). Overall, 23 (33.8%) patients developed DGF. The RTCA score was significantly lower in kidneys developing DGF -0.43 ±â€Š1.78 versus no DGF 0.91 ±â€Š2.17, P = 0.01. The Remuzzi score did not differ between DGF and no DGF, P = 0.13. Remuzzi score and RTCA score correlate inversely significantly; P = 0.004. In the multivariate analysis, solely RTCA score was revealed as a significant independent factor predicting DGF; P = 0.015, Wald = 5.95, odds ratio = 0.72, 95% confidence interval = 0.55 to 0.94. CONCLUSIONS: Our data demonstrate that RTCA is feasible and clinically meaningful. The RTCA score predicts DGF and is a valid option to be applied in renal transplantation.


Subject(s)
Delayed Graft Function/pathology , Kidney Transplantation/methods , Liver/pathology , Living Donors , Microscopy, Confocal/methods , Staining and Labeling/methods , Adult , Aged , Biopsy, Needle , Coloring Agents , Delayed Graft Function/diagnostic imaging , Donor Selection , Female , Graft Rejection , Graft Survival , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Liver/ultrastructure , Male , Middle Aged , Nephrectomy/methods , Pilot Projects , Preoperative Care/methods , Prognosis , Prospective Studies , Risk Assessment , Time Factors , Treatment Outcome
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