Publications by authors named "Henri G D Leuvenink"

133 Publications

Impact of Red Blood Cells on Function and Metabolism of Porcine Deceased Donor Kidneys During Normothermic Machine Perfusion.

Transplantation 2021 Aug 27. Epub 2021 Aug 27.

Department of Surgery, University Medical Center Groningen, University of Groningen, The Netherlands Department of Critical Care, University Medical Center Groningen, University of Groningen, The Netherlands Department of Pathology, University Medical Center Groningen, University of Groningen, The Netherlands Department of Surgery, Nuffield Department of Surgical Science, University of Oxford, United Kingdom IRTOMIT, INSERM U1082, Faculté de Médecine et de Pharmacie, Université de Poitiers, France Department for Surgical Research/General Surgery, University Hospital Essen, Germany.

Normothermic machine perfusion (NMP) protocols using blood-based solutions are commonly used in the assessment of kidneys prior to transplantation. This procedure is nevertheless limited by blood availability and warrants the search for alternatives. We compared a blood-based solution to a serum-like preservation solution (Aqix) enriched with colloids, with and without red blood cells (RBC). Porcine kidneys retrieved from an abattoir were subjected to 30 min of warm ischemia, followed by 3h of hypothermic oxygenated machine perfusion at 4°C. Subsequently, kidneys (n = 6 per group) were evaluated with NMP for 4h with 5 different solutions: Diluted blood, Aqix with bovine serum albumin (BSA) +/- RBC's; or Aqix with Dextran 40 +/- RBC's. Throughout NMP, markers of renal function and tubular metabolism were favorable in RBC's groups. Addition of RBC's resulted in a 4- to 6-fold higher oxygen consumption rates. Controls had significantly higher ATP levels post-NMP, exhibited decreased production of oxidative stress markers, and had the highest creatinine clearance. In conclusion, this study shows that addition of RBC's during NMP reduced renal injury, improved function, and was associated with increased renal metabolism. Although the RBC-BSA-supplemented Aqix solution was also able to support metabolism and renal function, a blood-based perfusion solution remains superior.
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http://dx.doi.org/10.1097/TP.0000000000003940DOI Listing
August 2021

Magnetic resonance imaging assessment of renal flow distribution patterns during ex vivo normothermic machine perfusion in porcine and human kidneys.

Transpl Int 2021 Sep;34(9):1643-1655

Department of Radiology, University of Groningen, University Medical Center, Groningen, The Netherlands.

Acceptance criteria of deceased donor organs have gradually been extended toward suboptimal quality, posing an urgent need for more objective pre-transplant organ assessment. Ex vivo normothermic machine perfusion (NMP) combined with magnetic resonance imaging (MRI) could assist clinicians in deciding whether a donor kidney is suitable for transplantation. Aim of this study was to characterize the regional distribution of perfusate flow during NMP, to better understand how ex vivo kidney assessment protocols should eventually be designed. Nine porcine and 4 human discarded kidneys underwent 3 h of NMP in an MRI-compatible perfusion setup. Arterial spin labeling scans were performed every 15 min, resulting in perfusion-weighted images that visualize intrarenal flow distribution. At the start of NMP, all kidneys were mainly centrally perfused and it took time for the outer cortex to reach its physiological dominant perfusion state. Calculated corticomedullary ratios based on the perfusion maps reached a physiological range comparable to in vivo observations, but only after 1 to 2 h after the start of NMP. Before that, the functionally important renal cortex appeared severely underperfused. Our findings suggest that early functional NMP quality assessment markers may not reflect actual physiology and should therefore be interpreted with caution.
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http://dx.doi.org/10.1111/tri.13991DOI Listing
September 2021

Proteomic analysis of machine perfusion solution from brain dead donor kidneys reveals that elevated complement, cytoskeleton and lipid metabolism proteins are associated with 1-year outcome.

Transpl Int 2021 Sep;34(9):1618-1629

Department of Surgery, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.

Assessment of donor kidney quality is based on clinical scores or requires biopsies for histological assessment. Noninvasive strategies to identify and predict graft outcome at an early stage are, therefore, needed. We evaluated the perfusate of donation after brain death (DBD) kidneys during nonoxygenated hypothermic machine perfusion (HMP). In particular, we compared perfusate protein profiles of good outcome (GO) and suboptimal outcome (SO) 1-year post-transplantation. Samples taken 15 min after the start HMP (T1) and before the termination of HMP (T2) were analysed using quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS). Hierarchical clustering of the 100 most abundant proteins showed discrimination between grafts with a GO and SO at T1. Elevated levels of proteins involved in classical complement cascades at both T1 and T2 and a reduced abundance of lipid metabolism at T1 and of cytoskeletal proteins at T2 in GO versus SO was observed. ATP-citrate synthase and fatty acid-binding protein 5 (T1) and immunoglobulin heavy variable 2-26 and desmoplakin (T2) showed 91% and 86% predictive values, respectively, for transplant outcome. Taken together, DBD kidney HMP perfusate profiles can distinguish between outcome 1-year post-transplantation. Furthermore, it provides insights into mechanisms that could play a role in post-transplant outcomes.
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http://dx.doi.org/10.1111/tri.13984DOI Listing
September 2021

Elevated plasma free thiols are associated with early and one-year graft function in renal transplant recipients.

PLoS One 2021 11;16(8):e0255930. Epub 2021 Aug 11.

Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark.

Background: Reduced free thiols in plasma are indicative of oxidative stress, which is an important contributor to ischaemia-reperfusion injury (IRI) in kidney transplantation leading to kidney damage and possibly delayed graft function (DGF). In a post-hoc, exploratory analysis of the randomised controlled CONTEXT trial, we investigated whether higher (i.e. less oxidised) plasma levels of free thiols as a biomarker of reduced oxidative stress are associated with a better initial graft function or a higher GFR.

Methods: Free thiol levels were measured in plasma at baseline, 30 and 90 minutes after reperfusion of the kidney as well as at Day 1, Day 5 and twelve months after kidney transplantation in 217 patients from the CONTEXT study. Free thiol levels were compared to the kidney graft function measured as the estimated time to a 50% reduction in plasma creatinine (tCr50), the risk of DGF and measured GFR (mGFR) at Day 5 and twelve months after transplantation.

Results: Higher levels of free thiols at Day 1 and Day 5 are associated with higher mGFR at Day 5 (p<0.001, r2adj. = 0.16; p<0.001, r2adj. = 0.25), as well as with mGFR at twelve months (p<0.001, r2adj. = 0.20; p<0.001, r2adj. = 0.16). However, plasma levels of free thiols at 30 minutes and 90 minutes, but not Day 1, were significantly higher among patients experiencing DGF.

Conclusion: Higher levels of plasma free thiols at Day 1 and Day 5, which are reflective of lower levels of oxidative stress, are associated with better early and late graft function in recipients of a kidney graft from deceased donors.

Trial Registration: ClinicalTrials.gov Identifier: NCT01395719.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255930PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357095PMC
August 2021

Hypothermic Machine Perfusion as a National Standard Preservation Method for Deceased Donor Kidneys.

Transplantation 2021 Jun 23. Epub 2021 Jun 23.

Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands Dutch Transplant Foundation, Leiden, The Netherlands Department of Surgery, Amsterdam Medical Center, Amsterdam, The Netherlands Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands Department of Nephrology, University Medical Center Utrecht, Utrecht, The Netherlands Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands Department of Nephrology, University Medical Center Groningen, Groningen, The Netherlands.

Background: Recently, continuous nonoxygenated hypothermic machine perfusion (HMP) has been implemented as standard preservation method for deceased donor kidneys in the Netherlands. This study was designed to assess the effect of the implementation of HMP on early outcomes after transplantation.

Methods: Kidneys donated in the Netherlands from 2016 to 2017 were intended to be preserved by HMP. A historical cohort (2010-2014) preserved by static cold storage (CS) was chosen as control group. Primary outcome was delayed graft function (DGF). Additional analyses were performed on safety, graft function and survival up until 2 years after transplantation.

Results: Data was collected on 2493 kidneys. Analyses showed significantly more DCD, pre-emptive and retransplants in the project cohort. Of the 681 kidneys that were transplanted during the project, 81% was preserved by HMP. No kidneys were discarded due to HMP related complications. DGF occurred in 38.2% of the project cohort versus 43.7% of the historical cohort (p <0.001), with a significantly shorter duration within the project cohort (7 versus 9 days, p = 0.003). Multivariate regression analysis showed an odds ratio of 0.69 (95% CI 0.553 - 0.855) for the risk of DGF when using HMP compared to CS (p = 0.001). There was no significant difference in kidney function, graft and recipient survival up until 2 years post transplantation.

Conclusions: This study showed that HMP as standard preservation method for deceased donor kidneys is safe and feasible. HMP was associated with a significant reduction of DGF.
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http://dx.doi.org/10.1097/TP.0000000000003845DOI Listing
June 2021

Hypothermic oxygenated machine perfusion of the human pancreas for clinical islet isolation: a prospective feasibility study.

Transpl Int 2021 Aug 4;34(8):1397-1407. Epub 2021 Jul 4.

Department of Surgery, University Medical Center Groningen, Groningen, the Netherlands.

Due to an increasing scarcity of pancreases with optimal donor characteristics, islet isolation centers utilize pancreases from extended criteria donors, such as from donation after circulatory death (DCD) donors, which are particularly susceptible to prolonged cold ischemia time (CIT). We hypothesized that hypothermic machine perfusion (HMP) can safely increase CIT. Five human DCD pancreases were subjected to 6 h of oxygenated HMP. Perfusion parameters, apoptosis, and edema were measured prior to islet isolation. Five human DBD pancreases were evaluated after static cold storage (SCS). Islet viability, and in vitro and in vivo functionality in diabetic mice were analyzed. Islets were isolated from HMP pancreases after 13.4 h [12.9-14.5] CIT and after 9.2 h [6.5-12.5] CIT from SCS pancreases. Histological analysis of the pancreatic tissue showed that HMP did not induce edema nor apoptosis. Islets maintained >90% viable during culture, and an appropriate in vitro and in vivo function in mice was demonstrated after HMP. The current study design does not permit to demonstrate that oxygenated HMP allows for cold ischemia extension; however, the successful isolation of functional islets from discarded human DCD pancreases after performing 6 h of oxygenated HMP indicates that oxygenated HMP may be a useful technology for better preservation of pancreases.
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http://dx.doi.org/10.1111/tri.13927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456912PMC
August 2021

Prolonged ex-vivo normothermic kidney perfusion: The impact of perfusate composition.

PLoS One 2021 18;16(5):e0251595. Epub 2021 May 18.

Department of Surgery-Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Normothermic machine perfusion (NMP) of donor kidneys provides the opportunity for improved graft preservation and objective pre-transplant ex-vivo organ assessment. Currently, a multitude of perfusion solutions exist for renal NMP. This study aimed to evaluate four different perfusion solutions side-by-side and determine the influence of different perfusate compositions on measured renal perfusion parameters. Porcine kidneys and blood were obtained from a slaughterhouse. Kidneys underwent NMP at 37°C for 7 hours, with 4 different perfusion solutions (n = 5 per group). Group 1 consisted of red blood cells (RBCs) and a perfusion solution based on Williams' Medium E. Group 2 consisted of RBCs, albumin and a balanced electrolyte composition. Group 3 contained RBCs and a medium based on a British clinical NMP solution. Group 4 contained RBCs and a medium used in 24-hour perfusion experiments. NMP flow patterns for solutions 1 and 2 were similar, solutions 3 and 4 showed lower but more stable flow rates. Thiobarbituric acid reactive substances were significantly higher in solution 1 and 4 compared to the other groups. Levels of injury marker N-acetyl-β-D glucosaminidase were significantly lower in solution 2 in comparison with solution 3 and 4. This study illustrates that the perfusate composition during NMP significantly impacts the measured perfusion and injury parameters and thus affects the interpretation of potential viability markers. Further research is required to investigate the individual influences of principal perfusate components to determine the most optimal conditions during NMP and eventually develop universal organ assessment criteria.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251595PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130974PMC
October 2021

Renal Normothermic Machine Perfusion: The Road Toward Clinical Implementation of a Promising Pretransplant Organ Assessment Tool.

Transplantation 2021 May 11. Epub 2021 May 11.

Department of Surgery - Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands Laboratory of Abdominal Transplantation, Transplantation Research Group, Department of Microbiology, Immunology, and Transplantation, KU Leuven, Leuven, Belgium Department of Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium.

The increased utilization of high-risk renal grafts for transplantation requires optimization of pretransplant organ assessment strategies. Current decision-making methods to accept an organ for transplantation lack overall predictive power and always contain an element of subjectivity. Normothermic machine perfusion (NMP) creates near-physiological conditions, which might facilitate a more objective assessment of organ quality prior to transplantation. NMP is rapidly gaining popularity, with various transplant centers developing their own NMP protocols and renal viability criteria. However, to date, no validated sets of on-pump viability markers exist nor are there unified NMP protocols. This review provides a critical overview of the fundamentals of current renal NMP protocols and proposes a framework to approach further development of ex vivo organ evaluation. We also comment on the potential logistical implications of routine clinical use of NMP, which is a more complex procedure compared to static cold storage or even hypothermic machine perfusion. Supplemental Visual Abstract; http://links.lww.com/TP/C232.
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http://dx.doi.org/10.1097/TP.0000000000003817DOI Listing
May 2021

Oxygenated End-Hypothermic Machine Perfusion in Expanded Criteria Donor Kidney Transplant: A Randomized Clinical Trial.

JAMA Surg 2021 Jun;156(6):517-525

Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.

Importance: Continuous hypothermic machine perfusion during organ preservation has a beneficial effect on graft function and survival in kidney transplant when compared with static cold storage (SCS).

Objective: To compare the effect of short-term oxygenated hypothermic machine perfusion preservation (end-HMPo2) after SCS vs SCS alone on 1-year graft survival in expanded criteria donor kidneys from donors who are brain dead.

Design, Setting, And Participants: In a prospective, randomized, multicenter trial, kidneys from expanded criteria donors were randomized to either SCS alone or SCS followed by end-HMPo2 prior to implantation with a minimum machine perfusion time of 120 minutes. Kidneys were randomized between January 2015 and May 2018, and analysis began May 2019. Analysis was intention to treat.

Interventions: On randomization and before implantation, deceased donor kidneys were either kept on SCS or placed on HMPo2.

Main Outcome And Measures: Primary end point was 1-year graft survival, with delayed graft function, primary nonfunction, acute rejection, estimated glomerular filtration rate, and patient survival as secondary end points.

Results: Centers in 5 European countries randomized 305 kidneys (median [range] donor age, 64 [50-84] years), of which 262 kidneys (127 [48.5%] in the end-HMPo2 group vs 135 [51.5%] in the SCS group) were successfully transplanted. Median (range) cold ischemia time was 13.2 (5.1-28.7) hours in the end-HMPo2 group and 12.9 (4-29.2) hours in the SCS group; median (range) duration in the end-HMPo2 group was 4.7 (0.8-17.1) hours. One-year graft survival was 92.1% (n = 117) in the end-HMPo2 group vs 93.3% (n = 126) in the SCS group (95% CI, -7.5 to 5.1; P = .71). The secondary end point analysis showed no significant between-group differences for delayed graft function, primary nonfunction, estimated glomerular filtration rate, and acute rejection.

Conclusions And Relevance: Reconditioning of expanded criteria donor kidneys from donors who are brain dead using end-HMPo2 after SCS does not improve graft survival or function compared with SCS alone. This study is underpowered owing to the high overall graft survival rate, limiting interpretation.

Trial Registration: isrctn.org Identifier: ISRCTN63852508.
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http://dx.doi.org/10.1001/jamasurg.2021.0949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060886PMC
June 2021

Molecular Aspects of Volatile Anesthetic-Induced Organ Protection and Its Potential in Kidney Transplantation.

Int J Mol Sci 2021 Mar 8;22(5). Epub 2021 Mar 8.

Department of Surgery, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.

Ischemia reperfusion injury (IRI) is inevitable in kidney transplantation and negatively impacts graft and patient outcome. Reperfusion takes place in the recipient and most of the injury following ischemia and reperfusion occurs during this reperfusion phase; therefore, the intra-operative period seems an attractive window of opportunity to modulate IRI and improve short- and potentially long-term graft outcome. Commonly used volatile anesthetics such as sevoflurane and isoflurane have been shown to interfere with many of the pathophysiological processes involved in the injurious cascade of IRI. Therefore, volatile anesthetic (VA) agents might be the preferred anesthetics used during the transplantation procedure. This review highlights the molecular and cellular protective points of engagement of VA shown in in vitro studies and in vivo animal experiments, and the potential translation of these results to the clinical setting of kidney transplantation.
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http://dx.doi.org/10.3390/ijms22052727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962839PMC
March 2021

Ex Vivo Perfusion With Methylprednisolone Attenuates Brain Death-induced Lung Injury in Rats.

Transplant Direct 2021 Apr 16;7(4):e682. Epub 2021 Mar 16.

Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands.

The onset of brain death (BD) leads to the deterioration of potential donor lungs. Methylprednisolone is considered to increase lung oxygenation capacity and enhance the procurement yield of donor lungs, when applied in situ, during donor management. However, whether BD-induced lung damage is ameliorated upon treatment with methylprednisolone during acellular ex vivo lung perfusion (EVLP), remains unknown. We aimed to investigate whether the quality of lungs from brain-dead donors improves upon methylprednisolone treatment during EVLP.

Methods: Rat lungs were randomly assigned to 1 of 3 experimental groups (n = 8/group): (1) healthy, directly procured lungs subjected to EVLP; (2) lungs from brain-dead rats subjected to cold storage and EVLP; and (3) lungs from brain-dead rats subjected to cold storage and EVLP with 40 mg methylprednisolone added to the perfusate. Ventilation and perfusion parameters, histology, edema formation, metabolic profile, and inflammatory status of lungs were investigated.

Results: Methylprednisolone treated lungs from brain-dead donors improved positive inspiratory pressures needed to maintain tidal volumes of 7 mL/kg of body weight, which was 25.6 ± 5.8 cm HO in untreated lungs and 18.0 ± 3.0 cm HO in methylprednisolone treated lungs, after 6 h EVLP. Furthermore, dynamic lung compliance increased upon methylprednisolone treatment, with values of 0.11 ± 0.05 mL/cm HO versus 0.18 ± 0.04 mL/cm HO after 6 h of EVLP. Methylprednisolone treatment ameliorated the amount of lung edema, as corroborated by a reduction of 0.7 in the wet/dry ratio. Although glucose consumption levels were comparable, the BD-induced cumulative lactate production decreased from 0.44 ± 0.26 to 0.11 ± 0.16 mmol/L upon methylprednisolone treatment. Finally, BD-induced inflammatory status was reduced upon methylprednisolone treatment compared to untreated lungs from brain-dead donors, as reflected by lower proinflammatory gene expression levels of IL-1β, IL-6 and MCP-1, and IL-6 perfusate levels.

Conclusions: We showed that methylprednisolone treatment during EVLP attenuates BD-induced lung injury.
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http://dx.doi.org/10.1097/TXD.0000000000001141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969243PMC
April 2021

Machine-perfused donor kidneys as a source of human renal endothelial cells.

Am J Physiol Renal Physiol 2021 05 15;320(5):F947-F962. Epub 2021 Mar 15.

Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Renal endothelial cells (ECs) play crucial roles in vasorelaxation, ultrafiltration, and selective transport of electrolytes and water, but also in leakage of the glomerular filtration barrier and inflammatory processes like complement activation and leukocyte recruitment. In addition, they are target cells for both cellular and antibody-mediated rejection in the transplanted kidney. To study the molecular and cellular processes underlying EC behavior in renal disease, well-characterized primary renal ECs are indispensible. In this report, we describe a straightforward procedure to isolate ECs from the perfusion fluid of human donor kidneys by a combination of negative selection of monocytes/macrophages, positive selection by CD31 Dynabeads, and propagation in endothelium-specific culture medium. Thus, we isolated and propagated renal ECs from 102 donor kidneys, representative of all blood groups and major human leukocyte antigen (HLA) class I and II antigens. The obtained ECs were positive for CD31 and von Willebrand factor, expressed other endothelial markers such as CD34, VEGF receptor-2, TIE2, and plasmalemmal vesicle associated protein-1 to a variable extent, and were negative for the monocyte marker CD14 and lymphatic endothelial marker podoplanin. HLA class II was either constitutively expressed or could be induced by interferon-γ. Furthermore, as a proof of principle, we showed the diagnostic value of this renal endothelial biobank in renal endothelium-specific cross-matching tests for HLA antibodies. We describe a new and widely accessible approach to obtain human primary renal endothelial cells in a standardized fashion, by isolating from the perfusate of machine-perfused donor kidneys. Characterization of the cells showed a mixed population originating from different compartments of the kidney. As a proof of principle, we demonstrated a possible diagnostic application in an endothelium-specific cross-match. Next to transplantation, we foresee further applications in the field renal endothelial research.
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http://dx.doi.org/10.1152/ajprenal.00541.2020DOI Listing
May 2021

Methylprednisolone Treatment in Brain Death-Induced Lung Inflammation-A Dose Comparative Study in Rats.

Front Pharmacol 2021 22;12:587003. Epub 2021 Feb 22.

Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

The process of brain death (BD) leads to a pro-inflammatory state of the donor lung, which deteriorates its quality. In an attempt to preserve lung quality, methylprednisolone is widely recommended in donor lung management. However, clinical treatment doses vary and the dose-effect relation of methylprednisolone on BD-induced lung inflammation remains unknown. The aim of this study was to investigate the effect of three different doses methylprednisolone on the BD-induced inflammatory response. BD was induced in rats by inflation of a Fogarty balloon catheter in the epidural space. After 60 min of BD, saline or methylprednisolone (low dose (5 mg/kg), intermediate dose (12.5 mg/kg) or high dose (22.5 mg/kg)) was administered intravenously. The lungs were procured and processed after 4 h of BD. Inflammatory gene expressions were analyzed by RT-qPCR and influx of neutrophils and macrophages were quantified with immunohistochemical staining. Methylprednisolone treatment reduced neutrophil chemotaxis as demonstrated by lower IL-8-like CINC-1 and E-selectin levels, which was most evident in rats treated with intermediate and high doses methylprednisolone. Macrophage chemotaxis was attenuated in all methylprednisolone treated rats, as corroborated by lower MCP-1 levels compared to saline treated rats. Thereby, all doses methylprednisolone reduced TNF-α, IL-6 and IL-1β tissue levels. In addition, intermediate and high doses methylprednisolone induced a protective anti-inflammatory response, as reflected by upregulated IL-10 expression when compared to saline treated brain-dead rats. We showed that intermediate and high doses methylprednisolone share most potential to target BD-induced lung inflammation in rats. Considering possible side effects of high doses methylprednisolone, we conclude from this study that an intermediate dose of 12.5 mg/kg methylprednisolone is the optimal treatment dose for BD-induced lung inflammation in rats, which reduces the pro-inflammatory state and additionally promotes a protective, anti-inflammatory response.
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http://dx.doi.org/10.3389/fphar.2021.587003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937885PMC
February 2021

Improved Normothermic Machine Perfusion After Short Oxygenated Hypothermic Machine Perfusion of Ischemically Injured Porcine Kidneys.

Transplant Direct 2021 Feb 15;7(2):e653. Epub 2021 Jan 15.

Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Background: In an era where global kidney shortage has pushed the field of transplantation towards using more marginal donors, modified kidney preservation techniques are currently being reviewed. Some techniques require further optimization before implementation in full scale transplantation studies. Using a porcine donation after circulatory death kidney model, we investigated whether initial kidney hemodynamics improved during normothermic machine perfusion if this was preceded by a short period of oxygenated hypothermic machine perfusion (oxHMP) rather than static cold storage (SCS).

Methods: Kidneys subjected to 75 minutes of warm ischemia were randomly assigned to either SCS (n = 4) or SCS + oxHMP (n = 4), with a total cold storage time of 240 minutes. Cold preservation was followed by 120 minutes of normothermic machine perfusion with continuous measurement of hemodynamic parameters and renal function.

Results: oxHMP preserved kidneys maintained significantly lower renal resistance throughout the normothermic machine perfusion period compared to SCS kidneys ( < 0.001), reaching lowest levels at 60 minutes with means of 0.71 ± 0.35 mm Hg/mL/min/100 g (SCS) and 0.45 ± 0.15 mm Hg/mL/min/100 g (oxHMP). Accordingly, the oxHMP group had a higher mean renal blood flow versus SCS kidneys ( < 0.001). oxHMP kidneys had higher oxygen consumption during normothermic machine perfusion compared to SCS preserved kidneys ( < 0.001). Creatinine clearance remained similar between groups ( = 0.665).

Conclusions: Preceding oxHMP significantly improved initial normothermic machine perfusion hemodynamics and increased total oxygen consumption. With the long period of warm ischemia, immediate kidney function was not observed, reflected by the findings of low creatinine clearance in both groups.
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http://dx.doi.org/10.1097/TXD.0000000000001108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817286PMC
February 2021

Mesenchymal stromal cell treatment of donor kidneys during ex vivo normothermic machine perfusion: A porcine renal autotransplantation study.

Am J Transplant 2021 07 8;21(7):2348-2359. Epub 2021 Mar 8.

Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Normothermic machine perfusion (NMP) of injured kidneys offers the opportunity for interventions to metabolically active organs prior to transplantation. Mesenchymal stromal cells (MSCs) can exert regenerative and anti-inflammatory effects in ischemia-reperfusion injury. The aims of this study were to evaluate the safety and feasibility of MSC treatment of kidneys during NMP using a porcine autotransplantation model, and examine potential MSC treatment-associated kidney improvements up to 14 days posttransplant. After 75 min of kidney warm ischemia, four experimental groups of n = 7 underwent 14 h of oxygenated hypothermic machine perfusion. In three groups this was followed by 240 min of NMP with infusion of vehicle, 10 million porcine, or 10 million human adipose-derived MSCs. All kidneys were autotransplanted after contralateral nephrectomy. MSC treatment did not affect perfusion hemodynamics during NMP or cause adverse effects at reperfusion, with 100% animal survival. MSCs did not affect plasma creatinine, glomerular filtration rate, neutrophil gelatinase-associated lipocalin concentrations or kidney damage assessed by histology during the 14 days, and MSCs retention was demonstrated in renal cortex. Infusing MSCs during ex vivo NMP of porcine kidneys was safe and feasible. Within the short posttransplant follow-up period, no beneficial effects of ex vivo MSC therapy could be demonstrated.
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http://dx.doi.org/10.1111/ajt.16473DOI Listing
July 2021

Rat donor lung quality deteriorates more after fast than slow brain death induction.

PLoS One 2020 30;15(11):e0242827. Epub 2020 Nov 30.

Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Donor brain death (BD) is initiated by an increase in intracranial pressure (ICP), which subsequently damages the donor lung. In this study, we investigated whether the speed of ICP increase affects quality of donor lungs, in a rat model for fast versus slow BD induction. Rats were assigned to 3 groups: 1) control, 2) fast BD induction (ICP increase over 1 min) or 3) slow BD induction (ICP increase over 30 min). BD was induced by epidural inflation of a balloon catheter. Brain-dead rats were sacrificed after 0.5 hours, 1 hour, 2 hours and 4 hours to study time-dependent changes. Hemodynamic stability, histological lung injury and inflammatory status were investigated. We found that fast BD induction compromised hemodynamic stability of rats more than slow BD induction, reflected by higher mean arterial pressures during the BD induction period and an increased need for hemodynamic support during the BD stabilization phase. Furthermore, fast BD induction increased histological lung injury scores and gene expression levels of TNF-α and MCP-1 at 0.5 hours after induction. Yet after donor stabilization, inflammatory status was comparable between the two BD models. This study demonstrates fast BD induction deteriorates quality of donor lungs more on a histological level than slow BD induction.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242827PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704005PMC
January 2021

Corrigendum to 'Propofol-based anaesthesia versus sevoflurane-based anaesthesia for living donor kidney transplantation: results of the VAPOR-1 randomized controlled trial' (Br J Anaesth 2017; 118: 720-32).

Br J Anaesth 2021 01 20;126(1):340-341. Epub 2020 Nov 20.

Department of Anaesthesiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands; Department of Basic and Applied Medical Sciences, Ghent University, Ghent, Belgium.

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http://dx.doi.org/10.1016/j.bja.2020.10.024DOI Listing
January 2021

Oxygenated versus standard cold perfusion preservation in kidney transplantation (COMPARE): a randomised, double-blind, paired, phase 3 trial.

Lancet 2020 11;396(10263):1653-1662

Department of Surgery, University Medical Center Groningen, Groningen, Netherlands; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK; Transplant Center, Leiden University Medical Center, Leiden, Netherlands.

Background: Deceased donor kidneys are preserved in cold hypoxic conditions. Providing oxygen during preservation might improve post-transplant outcomes, particularly for kidneys subjected to greater degrees of preservation injury. This study aimed to investigate whether supplemental oxygen during hypothermic machine perfusion (HMP) could improve the outcome of kidneys donated after circulatory death.

Methods: This randomised, double-blind, paired, phase 3 trial was done in 19 European transplant centres. Kidney pairs from donors aged 50 years or older, donated after circulatory death, were eligible if both kidneys were transplanted into two different recipients. One kidney from each donor was randomly assigned using permuted blocks to oxygenated hypothermic machine perfusion (HMPO), the other to HMP without oxygenation. Perfusion was maintained from organ retrieval to implantation. The primary outcome was 12-month estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration equation in pairs of donated kidneys in which both transplanted kidneys were functioning at the end of follow-up. Safety outcomes were reported for all transplanted kidneys. Intention-to-treat analyses were done. This trial is registered with the ISRCTN Registry, ISRCTN32967929, and is now closed.

Findings: Between March 15, 2015, and April 11, 2017, 197 kidney pairs were randomised with 106 pairs transplanted into eligible recipients. 23 kidney pairs were excluded from the primary analysis because of kidney failure or patient death. Mean eGFR at 12 months was 50·5 mL/min per 1·73 m (SD 19·3) in the HMPO group versus 46·7 mL/min per 1·73m (17·1) in HMP (mean difference 3·7 mL/min per 1·73m, 95% CI -1·0 to 8·4; p=0·12). Fewer severe complications (Clavien-Dindo grade IIIb or more) were reported in the HMPO group (46 of 417, 11%, 95% CI 8% to 14%) than in the HMP group (76 of 474, 16%, 13% to 20%; p=0·032). Graft failure was lower with HMPO (three [3%] of 106) compared with HMP (11 [10%] of 106; hazard ratio 0·27, 95% CI 0·07 to 0·95; p=0·028).

Interpretation: HMPO of kidneys donated after circulatory death is safe and reduces post-transplant complications (grade IIIb or more). The 12-month difference in eGFR between the HMPO and HMP groups was not significant when both kidneys from the same donor were still functioning 1-year post-transplant, but potential beneficial effects of HMPO were suggested by analysis of secondary outcomes.

Funding: European Commission 7th Framework Programme.
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http://dx.doi.org/10.1016/S0140-6736(20)32411-9DOI Listing
November 2020

Regulatory T cells engineered with TCR signaling-responsive IL-2 nanogels suppress alloimmunity in sites of antigen encounter.

Sci Transl Med 2020 11;12(569)

Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Adoptive cell transfer of ex vivo expanded regulatory T cells (T) has shown immense potential in animal models of auto- and alloimmunity. However, the effective translation of such T therapies to the clinic has been slow. Because T homeostasis is known to require continuous T cell receptor (TCR) ligation and exogenous interleukin-2 (IL-2), some investigators have explored the use of low-dose IL-2 injections to increase endogenous T responses. Systemic IL-2 immunotherapy, however, can also lead to the activation of cytotoxic T lymphocytes and natural killer cells, causing adverse therapeutic outcomes. Here, we describe a drug delivery platform, which can be engineered to autostimulate T with IL-2 in response to TCR-dependent activation, and thus activate these cells in sites of antigen encounter. To this end, protein nanogels (NGs) were synthesized with cleavable bis(-hydroxysuccinimide) cross-linkers and IL-2/Fc fusion (IL-2) proteins to form particles that release IL-2 under reducing conditions, as found at the surface of T cells receiving stimulation through the TCR. T surface-conjugated with IL-2 NGs were found to have preferential, allograft-protective effects relative to unmodified T or T stimulated with systemic IL-2. We demonstrate that murine and human NG-modified T carrying an IL-2 cargo perform better than conventional T in suppressing alloimmunity in murine and humanized mouse allotransplantation models. In all, the technology presented in this study has the potential to improve T transfer therapy by enabling the regulated spatiotemporal provision of IL-2 to antigen-primed T.
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http://dx.doi.org/10.1126/scitranslmed.aaw4744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8519505PMC
November 2020

Renal Trapping in Accidental Metformin Intoxication.

Kidney Int Rep 2020 Sep 18;5(9):1525-1528. Epub 2020 Jun 18.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1016/j.ekir.2020.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486141PMC
September 2020

Increasing metformin concentrations and its excretion in both rat and porcine ex vivo normothermic kidney perfusion model.

BMJ Open Diabetes Res Care 2020 08;8(1)

Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Introduction: Metformin can accumulate and cause lactic acidosis in patients with renal insufficiency. Metformin is known to inhibit mitochondria, while renal secretion of the drug by proximal tubules indirectly requires energy. We investigated whether addition of metformin before or during ex vivo isolated normothermic machine perfusion (NMP) of porcine and rat kidneys affects its elimination.

Research Design And Methods: First, Lewis rats were pretreated with metformin or saline the day before nephrectomy. Subsequently, NMP of the kidney was performed for 90 min. Metformin was added to the perfusion fluid in one of three different concentrations (none, 30 mg/L or 300 mg/L). Second, metformin was added in increasing doses to the perfusion fluid during 4 hours of NMP of porcine kidneys. Metformin concentration was determined in the perfusion fluid and urine by liquid chromatography-tandem mass spectrometry.

Results: Metformin clearance was approximately 4-5 times higher than creatinine clearance in both models, underscoring secretion of the drug. Metformin clearance at the end of NMP in rat kidneys perfused with 30 mg/L was lower than in metformin pretreated rats without the addition of metformin during perfusion (both p≤0.05), but kidneys perfused with 300 mg/L trended toward lower metformin clearance (p=0.06). Creatinine clearance was not different between treatment groups. During NMP of porcine kidneys, metformin clearance peaked at 90 min of NMP (18.2±13.7 mL/min/100 g). Thereafter, metformin clearance declined, while creatinine clearance remained stable. This observation can be explained by saturation of metformin transporters with a Michaelis-Menten constant (95% CI) of 23.0 (10.0 to 52.3) mg/L.

Conclusions: Metformin was secreted during NMP of both rat and porcine kidneys. Excretion of metformin decreased under increasing concentrations of metformin, which might be explained by saturation of metformin transporters rather than a self-inhibitory effect. It remains unknown whether a self-inhibitory effect contributes to metformin accumulation in humans with longer exposure times.
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http://dx.doi.org/10.1136/bmjdrc-2019-000816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437879PMC
August 2020

Treating Ischemically Damaged Porcine Kidneys with Human Bone Marrow- and Adipose Tissue-Derived Mesenchymal Stromal Cells During Ex Vivo Normothermic Machine Perfusion.

Stem Cells Dev 2020 10 2;29(20):1320-1330. Epub 2020 Sep 2.

Department of Surgery-Organ Donation and Transplantation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Pretransplant normothermic machine perfusion (NMP) of donor kidneys offers the unique opportunity to perform active interventions to an isolated renal graft before transplantation. There is increasing evidence that mesenchymal stromal cells (MSCs) could have a paracrine/endocrine regenerative effect on ischemia-reperfusion injury. The purpose of this study was to determine which cytokines are secreted by MSCs during NMP of a porcine kidney. Viable porcine kidneys and autologous whole blood were obtained from a slaughterhouse. Warm ischemia time was standardized at 20 min and subsequent hypothermic machine perfusion was performed during 2-3 h. Thereafter, kidneys were machine perfused at 37°C during 7 h. After 1 h of NMP, 0, 10 cultured human adipose tissue-derived MSCs, or 10 cultured bone marrow-derived MSCs were added ( = 5 per group). In a fourth experimental group, 7-h NMP was performed with 10 adipose tissue-derived MSCs, without a kidney in the circuit. Kidneys perfused with MSCs showed lower lactate dehydrogenase and neutrophil gelatinase-associated lipocalin levels in comparison with the control group. Also, elevated levels of human hepatocyte growth factor, interleukin (IL)-6, and IL-8 were found in the perfusate of the groups perfused with MSCs compared to the control groups. This study suggests that MSCs, in contact with an injured kidney during NMP, could lead to lower levels of injury markers and induce the release of immunomodulatory cytokines.
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http://dx.doi.org/10.1089/scd.2020.0024DOI Listing
October 2020

Brain death-induced lung injury is complement dependent, with a primary role for the classical/lectin pathway.

Am J Transplant 2021 03 4;21(3):993-1002. Epub 2020 Sep 4.

Department of Cardiothoracic Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

In brain-dead donors immunological activation occurs, which deteriorates donor lung quality. Whether the complement system is activated and which pathways are herein involved, remain unknown. We aimed to investigate whether brain death (BD)-induced lung injury is complement dependent and dissected the contribution of the complement activation pathways. BD was induced and sustained for 3 hours in wild-type (WT) and complement deficient mice. C3 mice represented total complement deficiency, C4 mice represented deficiency of the classical and lectin pathway, and factor properdin (P) mice represented alternative pathway deficiency. Systemic and local complement levels, histological lung injury, and pulmonary inflammation were assessed. Systemic and local complement levels were reduced in C3 mice. In addition, histological lung injury and inflammation were attenuated, as corroborated by influx of neutrophils and gene expressions of interleukin (IL)-6, IL-8-like KC, TNF-α, E-selectin, and MCP-1. In C4 mice, complement was reduced on both systemic and local levels and histological lung injury and inflammatory status were ameliorated. In P mice, histological lung injury was attenuated, though systemic and local complement levels, IL-6 and KC gene expressions, and neutrophil influx were not affected. We demonstrated that BD-induced lung injury is complement dependent, with a primary role for the classical/lectin activation pathway.
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http://dx.doi.org/10.1111/ajt.16231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984080PMC
March 2021

Metformin Preconditioning and Postconditioning to Reduce Ischemia Reperfusion Injury in an Isolated Ex Vivo Rat and Porcine Kidney Normothermic Machine Perfusion Model.

Clin Transl Sci 2021 01 31;14(1):222-230. Epub 2020 Jul 31.

Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Metformin may act renoprotective prior to kidney transplantation by reducing ischemia-reperfusion injury (IRI). This study examined whether metformin preconditioning and postconditioning during ex vivo normothermic machine perfusion (NMP) of rat and porcine kidneys affect IRI. In the rat study, saline or 300 mg/kg metformin was administered orally twice on the day before nephrectomy. After 15 minutes of warm ischemia, kidneys were preserved with static cold storage for 24 hours. Thereafter, 90 minutes of NMP was performed with the addition of saline or metformin (30 or 300 mg/L). In the porcine study, after 30 minutes of warm ischemia, kidneys were preserved for 3 hours with oxygenated hypothermic machine perfusion. Subsequently, increasing doses of metformin were added during 4 hours of NMP. Metformin preconditioning of rat kidneys led to decreased injury perfusate biomarkers and reduced proteinuria. Postconditioning of rat kidneys resulted, dose-dependently, in less tubular cell necrosis and vacuolation. Heat shock protein 70 expression was increased in metformin-treated porcine kidneys. In all studies, creatinine clearance was not affected. In conclusion, both metformin preconditioning and postconditioning can be done safely and improved rat and porcine kidney quality. Because the effects are minor, it is unknown which strategy might result in improved organ quality after transplantation.
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http://dx.doi.org/10.1111/cts.12846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877823PMC
January 2021

The First ITS Meeting.

Transplantation 2020 06;104(6):1114-1116

Division of Rheumatology, Department of Medicine, The University of Chicago, Chicago, IL.

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http://dx.doi.org/10.1097/TP.0000000000003132DOI Listing
June 2020

Changing the Organ Preservation Game.

Transplantation 2020 05;104(5):895-896

Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1097/TP.0000000000003076DOI Listing
May 2020

Organ-specific metabolic profiles of the liver and kidney during brain death and afterwards during normothermic machine perfusion of the kidney.

Am J Transplant 2020 09 15;20(9):2425-2436. Epub 2020 Jun 15.

Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

We investigated metabolic changes during brain death (BD) using hyperpolarized magnetic resonance (MR) spectroscopy and ex vivo graft glucose metabolism during normothermic isolated perfused kidney (IPK) machine perfusion. BD was induced in mechanically ventilated rats by inflation of an epidurally placed catheter; sham-operated rats served as controls. Hyperpolarized [1- C]pyruvate MR spectroscopy was performed to quantify pyruvate metabolism in the liver and kidneys at 3 time points during BD, preceded by injecting hyperpolarized[1- C]pyruvate. Following BD, glucose oxidation was measured using tritium-labeled glucose (d-6-3H-glucose) during IPK reperfusion. Quantitative polymerase chain reaction and biochemistry were performed on tissue/plasma. Immediately following BD induction, lactate increased in both organs (liver: eµ 0.21, 95% confidence interval [CI] [-0.27, -0.15]; kidney: eµ 0.26, 95% CI [-0.40, -0.12]. After 4 hours of BD, alanine production decreased in the kidney (eµ 0.14, 95% CI [0.03, 0.25], P < .05). Hepatic lactate and alanine profiles were significantly different throughout the experiment between groups (P < .01). During IPK perfusion, renal glucose oxidation was reduced following BD vs sham animals (eµ 0.012, 95% CI [0.004, 0.03], P < .001). No differences in enzyme activities were found. Renal gene expression of lactate-transporter MCT4 increased following BD (P < .01). In conclusion, metabolic processes during BD can be visualized in vivo using hyperpolarized magnetic resonance imaging and with glucose oxidation during ex vivo renal machine perfusion. These techniques can detect differences in the metabolic profiles of the liver and kidney following BD.
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http://dx.doi.org/10.1111/ajt.15885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496945PMC
September 2020

Normothermic machine perfusion of ischaemically damaged porcine kidneys with autologous, allogeneic porcine and human red blood cells.

PLoS One 2020 10;15(3):e0229566. Epub 2020 Mar 10.

Department of Surgery-Organ Donation and Transplantation, University Medical Center Groningen, Groningen, the Netherlands.

In porcine kidney auto-transplant models, red blood cells (RBCs) are required for ex-vivo normothermic machine perfusion (NMP). As large quantities of RBCs are needed for NMP, utilising autologous RBCs would imply lethal exsanguination of the pig that is donor and recipient-to-be in the same experiment. The purpose of this study was to determine if an isolated porcine kidney can also be perfused with allogeneic porcine or human RBCs instead. Porcine kidneys, autologous and allogeneic blood were obtained from a local slaughterhouse. Human RBCs (O-pos), were provided by our transfusion laboratory. Warm ischaemia time was standardised at 20 minutes and subsequent hypothermic machine perfusion lasted 1.5-2.5 hours. Next, kidneys underwent NMP at 37°C during 7 hours with Williams' Medium E and washed, leukocyte depleted RBCs of either autologous, allogeneic, or human origin (n = 5 per group). During perfusion all kidneys were functional and produced urine. No macroscopic adverse reactions were observed. Creatinine clearance during NMP was significantly higher in the human RBC group in comparison with the allogeneic group (P = 0.049) but not compared to the autologous group. The concentration of albumin in the urine was significantly higher in the human RBC group (P <0.001) compared to the autologous and allogeneic RBC group. Injury marker aspartate aminotransferase was significantly higher in the human RBC group in comparison with the allogeneic group (P = 0.040) but not in comparison with the autologous group. Renal histology revealed glomerular and tubular damage in all groups. Signs of pathological hyperfiltration and microvascular injury were only observed in the human RBC group. In conclusion, perfusion of porcine kidneys with RBCs of different origin proved technically feasible. However, laboratory analysis and histology revealed more damage in the human RBC group compared to the other two groups. These results indicate that the use of allogeneic RBCs is preferable to human RBCs in a situation where autologous RBCs cannot be used for NMP.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229566PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064242PMC
June 2020

Metformin Preconditioning Improves Hepatobiliary Function and Reduces Injury in a Rat Model of Normothermic Machine Perfusion and Orthotopic Transplantation.

Transplantation 2020 09;104(9):e271-e280

Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Background: Preconditioning of donor livers before organ retrieval may improve organ quality after transplantation. We investigated whether preconditioning with metformin reduces preservation injury and improves hepatobiliary function in rat donor livers during ex situ normothermic machine perfusion (NMP) and after orthotopic liver transplantation.

Methods: Lewis rats were administered metformin via oral gavage, after which a donor hepatectomy was performed followed by a standardized cold storage period of 4 hours. Graft assessment was performed using NMP via double perfusion of the hepatic artery and portal vein. In an additional experiment, rat donor livers preconditioned with metformin were stored on ice for 4 hours and transplanted to confirm postoperative liver function and survival. Data were analyzed and compared with sham-fed controls.

Results: Graft assessment using NMP confirmed that preconditioning significantly improved ATP production, markers for hepatobiliary function (total bile production, biliary bilirubin, and bicarbonate), and significantly lowered levels of lactate, glucose, and apoptosis. After orthotopic liver transplantation, metformin preconditioning significantly reduced transaminase levels.

Conclusions: Preconditioning with metformin lowers hepatobiliary injury and improves hepatobiliary function in an in situ and ex situ model of rat donor liver transplantation.
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http://dx.doi.org/10.1097/TP.0000000000003216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439933PMC
September 2020

Post-transplantation plasma malondialdehyde is associated with cardiovascular mortality in renal transplant recipients: a prospective cohort study.

Nephrol Dial Transplant 2020 03;35(3):512-519

Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: In renal transplant recipients (RTRs), cardiovascular mortality is the most common cause of long-term renal graft loss. Oxidative stress (OS) has been associated with cardiovascular disease and is known to be enhanced in RTRs. We aimed to prospectively investigate whether the concentration of the OS biomarker malondialdehyde (MDA) is associated with long-term risk of cardiovascular mortality in a large cohort of RTRs.

Methods: The plasma MDA concentration was measured using the thiobarbituric acid reaction assay in 604 extensively phenotyped RTRs with a functioning allograft for ≥1 year. The association between MDA and cardiovascular mortality was assessed using Cox proportional hazard regression analyses in the overall cohort and within subgroups according to significant effect modifiers.

Results: Median circulating MDA concentration at baseline was 5.38 [interquartile range (IQR) 4.31-6.45] μmol/L. During a follow-up period of 6.4 (IQR 5.6-6.8) years, 110 (18%) RTRs died, with 40% of deaths due to cardiovascular causes. MDA concentration was significantly associated with the risk for cardiovascular mortality {hazard ratio [HR] 1.31 [95% confidence interval (CI) 1.03-1.67] per 1-SD increment}, independent of adjustment for potential confounders, including renal function, immunosuppressive therapy, smoking status and blood pressure. The association between MDA concentration and the risk for cardiovascular mortality was stronger in RTRs with relatively lower plasma ascorbic acid concentrations [≤42.5 µmol/L; HR 1.79 (95% CI 1.30-2.48) per 1-SD increment] or relatively lower estimated glomerular filtration rates [≤45 mL/min/1.73 m2; HR 2.09 (95% CI 1.45-3.00) per 1-SD increment].

Conclusions: Circulating MDA concentration is independently associated with long-term risk for cardiovascular mortality, particularly in RTRs with relatively lower ascorbic acid concentrations or renal function. Further studies are warranted to elucidate whether OS-targeted interventions could decrease cardiovascular mortality in RTRs.
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http://dx.doi.org/10.1093/ndt/gfz288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056950PMC
March 2020
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