Transcriptome Analysis of Kidney Grafts Subjected to Normothermic Ex Vivo Perfusion Demonstrates an Enrichment of Mitochondrial Metabolism Genes

Urbanellis, Peter; McEvoy, Caitríona M.; Škrtić, Marko; Kaths, J. Moritz; Kollmann, Dagmar; Linares, Ivan; Ganesh, Sujani; Oquendo, Fabiola; Sharma, Manraj; Mazilescu, Laura; Goto, Toru; Noguchi, Yuki; Mucsi, István; Ghanekar, Anand; Bägli, Darius; Konvalinka, Ana; Selzner, Markus; Robinson, Lisa A.

doi:10.1097/txd.0000000000001157

Cited by 7 publications

(12 citation statements)

References 96 publications

(154 reference statements)

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“…The first porcine-organ studies used hypothermic conditions but with improvements to oxygenation and media, normothermic ex vivo organ perfusion was achieved. Ex Vivo Organ Perfusion (EVOP) systems have been developed for lung, liver and kidney [ 3 , 4 , 5 ]. The power of this system is revealed by studies that have demonstrated that donor human organs can be maintained on the EVOP system and then be successfully transplanted into patients.…”

Section: Introductionmentioning

confidence: 99%

“…The power of this system is revealed by studies that have demonstrated that donor human organs can be maintained on the EVOP system and then be successfully transplanted into patients. The clinical usefulness of EVOP is obvious, but it has also been used successfully as an alternative to large animal studies, where cell therapy, drug testing and disease analysis has been carried out [ 5 ]. Organs perfused on the EVOP system can be monitored and assayed in real time providing an opportunity to gain data not available during live animal studies.…”

Section: Introductionmentioning

confidence: 99%

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Ex Vivo Perfusion Using a Mathematical Modeled, Controlled Gas Exchange Self-Contained Bioreactor Can Maintain a Mouse Kidney for Seven Days

Won

Castillo-Prado

Tan

et al. 2022

Cells

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Regenerative medicine requires better pre-clinical tools in order to increase the efficiency of novel therapies transitioning to the clinic. Current monolayer cell culture methods are suboptimal for effectively testing new therapies and live mouse models are expensive, time consuming and require invasive procedures. Fetal organ culture, organoids, microfluidics and culture of thick sections of adult organs all aim to fill the knowledge gap between monolayer culture and live mouse studies. Here we report on an ex vivo organ perfusion system that can support whole adult mouse organs. Ex vivo perfusion of healthy and diseased mouse organs allows for real-time analysis that provides immediate feedback and accurate data collection throughout the experiment. Having a suitable normothermic ex vivo perfusion system for mouse organs provides a tool that will help contribute to our understanding of kidney physiology and disease and can take advantage of the many mouse models of human disease that already exist. Furthermore, an ex vivo kidney perfusion system can be used for testing novel cell therapies, drug screening, drug validation and for the detection of nephrotoxic substances. Critical to the success of mouse ex vivo organ perfusion is having a suitable bioreactor to maintain the organ. Here we have focused on the mouse kidney and mathematically modeled, built and validated a bioreactor that can maintain a kidney for 7 days. The long duration of the ex vivo perfusion will help to advance studies on kidney disease and can rapidly test for new regenerative medicine therapies compared to whole animal studies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ex Vivo Perfusion Using a Mathematical Modeled, Controlled Gas Exchange Self-Contained Bioreactor Can Maintain a Mouse Kidney for Seven Days

Won

Castillo-Prado

Tan

et al. 2022

Cells

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“…Fatty acid metabolism used in the generation of ATP by proximal tubular epithelial cells, genes involved in the tricarboxylic acid cycle, oxidative phosphorylation, amino acid synthesis and ATPase binding were all significantly upregulated. Pathways relating to small molecule transport, interferon signalling and chemokine signalling, binding and chemotaxis were enriched in NEVKP indicating recovery from ischaemic injury 60 . Furthermore, they noted that uromodulin expression was higher after NEVKP.…”

Section: Longer Periods Of Normothermic Machine Perfusionmentioning

confidence: 98%

“…They identified members of the peroxisome proliferator-activated receptors (PPAR) family including PPARA, PPARD and RXRA as upstream regulators. Urbanellis et al performed transcriptional profiling using microarrays in a similar model on samples taken on day 3 posttransplant 60 . NEVKP kidneys were compared to kidneys that were transplanted immediately with no preservation interval and kidneys that were cold stored.…”

Section: Longer Periods Of Normothermic Machine Perfusionmentioning

confidence: 99%

Advances in Normothermic Machine Perfusion of the Kidney: Evidence for Clinical Practice and Underlying Mechanistic Actions

Hosgood

Nicholson

2022

EJT

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“…Although cold anoxic storage aims to arrest cell metabolism, ex vivo perfusion at physiologic normothermic temperature (37 °C) provides a continuous flow of warmed, oxygenated perfusate containing nutritional substrates, thereby maintaining the metabolic activity of the tissue. 12 Normothermic red cell–based-perfusion of porcine kidneys at 37 °C improved early postoperative creatinine and urea clearance in DCD grafts. 13 In addition, normothermic ex vivo perfusion allows graft assessment, reconditioning, and repair.…”

Section: Introductionmentioning

confidence: 98%

Subnormothermic Ex Vivo Porcine Kidney Perfusion Improves Energy Metabolism: Analysis Using 31P Magnetic Resonance Spectroscopic Imaging

Agius

Songeon

Klauser

et al. 2022

Transplantation Direct

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Background. The ideal preservation temperature for donation after circulatory death kidney grafts is unknown. We investigated whether subnormothermic (22 °C) ex vivo kidney machine perfusion could improve kidney metabolism and reduce ischemia-reperfusion injury. Methods. To mimic donation after circulatory death procurement, kidneys from 45-kg pigs underwent 60 min of warm ischemia. Kidneys were then perfused ex vivo for 4 h with Belzer machine perfusion solution UW at 22 °C or at 4 °C before transplantation. Magnetic resonance spectroscopic imaging coupled with LCModel fitting was used to assess energy metabolites. Kidney perfusion was evaluated with dynamic-contrast enhanced MRI. Renal biopsies were collected at various time points for histopathologic analysis. Results. Total adenosine triphosphate content was 4 times higher during ex vivo perfusion at 22 °C than at 4 °C perfusion. At 22 °C, adenosine triphosphate levels increased during the first hours of perfusion but declined afterward. Similarly, phosphomonoesters, containing adenosine monophosphate, were increased at 22 °C and then slowly consumed over time. Compared with 4 °C, ex vivo perfusion at 22 °C improved cortical and medullary perfusion. Finally, kidney perfusion at 22 °C reduced histological lesions after transplantation (injury score: 22 °C: 10.5 ± 3.5; 4 °C: 18 ± 2.25 over 30). Conclusions. Ex vivo kidney perfusion at 22°C improved graft metabolism and protected from ischemia-reperfusion injuries upon transplantation. Future clinical studies will need to define the benefits of subnormothermic perfusion in improving kidney graft function and patient’s survival.

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Transcriptome Analysis of Kidney Grafts Subjected to Normothermic Ex Vivo Perfusion Demonstrates an Enrichment of Mitochondrial Metabolism Genes

Abstract: Supplemental Digital Content is available in the text.

Cited by 7 publications

References 96 publications

Ex Vivo Perfusion Using a Mathematical Modeled, Controlled Gas Exchange Self-Contained Bioreactor Can Maintain a Mouse Kidney for Seven Days

Ex Vivo Perfusion Using a Mathematical Modeled, Controlled Gas Exchange Self-Contained Bioreactor Can Maintain a Mouse Kidney for Seven Days

Advances in Normothermic Machine Perfusion of the Kidney: Evidence for Clinical Practice and Underlying Mechanistic Actions

Subnormothermic Ex Vivo Porcine Kidney Perfusion Improves Energy Metabolism: Analysis Using 31P Magnetic Resonance Spectroscopic Imaging

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