Normothermic Ex Vivo Kidney Perfusion Reduces Warm Ischemic Injury of Porcine Kidney Grafts Retrieved After Circulatory Death

Hamar, Mátyás; Urbanellis, Peter; Kaths, Moritz; Kollmann, Dagmar; Linares, Ivan; Ganesh, Sujani; Wiebe, Aryn; Cen, Jun Yu; Yip, Paul; John, Rohan; Konvalinka, Ana; Mucsi, István; Ghanekar, Anand; Bägli, Darius; Grant, David; Robinson, Lisa A.; Selzner, Markus

doi:10.1097/tp.0000000000002245

Cited by 34 publications

(38 citation statements)

References 23 publications

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“…Two biopsies with insufficient protein yield (<100 g) to generate comparable results to the remaining biopsies were excluded. As previously reported by our group, 42 NEVKP-preserved grafts demonstrated superior kidney function after heterotopic autotransplantation compared to SCS-preserved grafts, with significantly lower serum creatinine (SCr) post-operatively in the NEVKP group compared to the SCS ( Figure 1B)(F-test, p<2.23x10 -15 ). Light microscopy demonstrated normal histology at baseline, with mild tubular injury in both groups at 30minutes post-reperfusion, slightly more prominent in SCS ( Figure 1C), as previously reported in this model.…”

Section: Proteomic Analysis Of Nevkp and Scs Biopsiessupporting

confidence: 78%

“…Light microscopy demonstrated normal histology at baseline, with mild tubular injury in both groups at 30minutes post-reperfusion, slightly more prominent in SCS ( Figure 1C), as previously reported in this model. 42 Tubular injury and dilatation was evident at POD3, and was more severe in SCS-treated kidneys ( Figure 1C). Figure 1D.…”

Section: Proteomic Analysis Of Nevkp and Scs Biopsiesmentioning

confidence: 96%

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Normothermic Ex-vivo Kidney Perfusion in a Porcine Auto-Transplantation Model Preserves the Expression of Key Mitochondrial Proteins: An Unbiased Proteomics Analysis

McEvoy

Clotet-Freixas

Tokár

et al. 2020

Preprint

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Normothermic ex-vivo kidney perfusion (NEVKP) results in significantly improved graft function in porcine auto-transplant models of DCD injury compared to static cold storage (SCS); however, the molecular mechanisms underlying these beneficial effects remain unclear. We performed an unbiased proteomics analysis of 28 kidney biopsies obtained at 3 time points from pig kidneys subjected to 30-minutes of warm ischemia, followed by 8 hours of NEVKP or SCS, and auto-transplantation. 70/6593 proteins quantified were differentially expressed between NEVKP and SCS groups (FDR<0.05). Proteins increased in NEVKP mediated key metabolic processes including fatty acid β-oxidation, the TCA-cycle and oxidative phosphorylation. Comparison of our findings with external datasets of ischemia-reperfusion, and other models of kidney injury confirmed that 47 of our proteins represent a common signature of kidney injury reversed or attenuated by NEVKP. We validated key metabolic proteins (ETFB, CPT2) by immunoblotting. Transcription factor databases identified PPARGC1A, PPARA/G/D and RXRA/B as the upstream regulators of our dataset, and we confirmed their increased expression in NEVKP with RT-PCR. The proteome-level changes observed in NEVKP mediate critical metabolic pathways that may explain the improved graft function observed. These effects may be coordinated by PPAR-family transcription factors, and may represent novel therapeutic targets in ischemia-reperfusion injury.

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Section: Proteomic Analysis Of Nevkp and Scs Biopsiessupporting

confidence: 78%

Section: Proteomic Analysis Of Nevkp and Scs Biopsiesmentioning

confidence: 96%

Normothermic Ex-vivo Kidney Perfusion in a Porcine Auto-Transplantation Model Preserves the Expression of Key Mitochondrial Proteins: An Unbiased Proteomics Analysis

McEvoy

Clotet-Freixas

Tokár

et al. 2020

Preprint

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“…Encouraging data about long‐term NMP in the kidney have been reported by Selzner's group at the University of Toronto using an experimental DBD and DCD porcine model. They demonstrated that longer periods of up to 16‐h of NMP are superior to both SCS alone and short‐duration NMP in terms of both tubular injury and post‐transplant organ function .…”

Section: Perfusion and Re‐conditioning Methods For Abdominal Organsmentioning

confidence: 99%

The future of organ perfusion and re‐conditioning

et al. 2019

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Summary Organ preservation and re‐conditioning using machine perfusion technologies continue to generate promising results in terms of viability assessment, organ utilization and improved initial graft function. Here, we summarize the latest findings and study the results of ex‐vivo/ex‐situ hypothermic (HMP) and normothermic machine perfusion (NMP) in the area of abdominal organ transplantation (kidney, liver, pancreas and intestine). We also consider the potential role of normothermic regional perfusion (NRP) to re‐condition donors after circulatory death organs before retrieval. The findings from clinical studies reported to date suggest that machine perfusion will offer real benefits when compared with conventional cold preservation. Several randomized trials are expected to report their findings within the next 2 years which may shed light on the relative merits of different perfusion methods and could indicate which perfusion parameters may be most useful to predict organ quality and viability. Further work is needed to identify composite endpoints that are relevant for transplanted organs that have undergone machine preservation. Multi‐centre trials to compare and analyse the combinations of NRP followed by HMP and/or NMP, either directly after organ retrieval using transportable devices or when back‐to‐base, are needed. The potential applications of machine preservation technology beyond the field of solid organ transplantation are also considered.

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“…While technically more complex, its advantages include the reduction of cold ischemia, as well as increased metabolic activity, while providing options to assess renal function and modify/repair grafts prior to transplantation. In the second millennium, this technology was widely tested in Europe, Canada, and United States [39], demonstrating better function and regeneration compared to CS [40] or HMP [41]. Hamar et al demonstrated that a porcine kidney exposed to 30 min of warm ischemia (WI) + 8 h EVNP had lower daily serum creatinine levels and better regeneration markers compared to grafts exposed to WI + 8 h CS [40].…”

Section: Alternative Preservation Temperaturesmentioning

confidence: 99%

“…In the second millennium, this technology was widely tested in Europe, Canada, and United States [39], demonstrating better function and regeneration compared to CS [40] or HMP [41]. Hamar et al demonstrated that a porcine kidney exposed to 30 min of warm ischemia (WI) + 8 h EVNP had lower daily serum creatinine levels and better regeneration markers compared to grafts exposed to WI + 8 h CS [40]. Metcalfe et al observed superior graft function with porcine kidneys at 38 • C during 16 h of autologous blood perfusion versus HMP [41].…”

Section: Alternative Preservation Temperaturesmentioning

confidence: 99%

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

Giraud

Thuillier

Cau

et al. 2020

IJMS

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

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Normothermic Ex Vivo Kidney Perfusion Reduces Warm Ischemic Injury of Porcine Kidney Grafts Retrieved After Circulatory Death

Cited by 34 publications

References 23 publications

Normothermic Ex-vivo Kidney Perfusion in a Porcine Auto-Transplantation Model Preserves the Expression of Key Mitochondrial Proteins: An Unbiased Proteomics Analysis

Normothermic Ex-vivo Kidney Perfusion in a Porcine Auto-Transplantation Model Preserves the Expression of Key Mitochondrial Proteins: An Unbiased Proteomics Analysis

The future of organ perfusion and re‐conditioning

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

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