Metabolite-enhanced normothermic machine perfusion improves kidney transplant viability
Jan Czogalla, Fabian Hausmann, Simon Lagies, Sydney E. Gies, Sabrina Christiansen, Nico Kaiser, Fabian Haas, Yusuke Okabayashi, Dominik Kylies, Smilla Hofmann, Rossana Franzin, Niklas Sabra, Sarah Bouari, Yitian Fang, Gisela Ambagtsheer, Ilka Edenhofer, Silvia Chilla, Anne K. Mühlig, Marina Zimmermann, Milagros N. Wong, Takashi Yokoo, Oliver Kretz, Maja Lindenmeyer, Florian Grahammer, Martin J. Hoogduijn, Ron de Bruin, Malte Kuehl, Sonja Hänzelmann, Bernd Kammerer, Loreto Gesualdo, Stefan Bonn, Robert C. Minnee, Tobias B. Huber, Victor G. Puelles
Jan Czogalla, Fabian Hausmann, Simon Lagies, Sydney E. Gies, Sabrina Christiansen, Nico Kaiser, Fabian Haas, Yusuke Okabayashi, Dominik Kylies, Smilla Hofmann, Rossana Franzin, Niklas Sabra, Sarah Bouari, Yitian Fang, Gisela Ambagtsheer, Ilka Edenhofer, Silvia Chilla, Anne K. Mühlig, Marina Zimmermann, Milagros N. Wong, Takashi Yokoo, Oliver Kretz, Maja Lindenmeyer, Florian Grahammer, Martin J. Hoogduijn, Ron de Bruin, Malte Kuehl, Sonja Hänzelmann, Bernd Kammerer, Loreto Gesualdo, Stefan Bonn, Robert C. Minnee, Tobias B. Huber, Victor G. Puelles
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Research Article Cell biology Metabolism Nephrology

Metabolite-enhanced normothermic machine perfusion improves kidney transplant viability

Abstract

Normothermic machine perfusion (NMP) has become a valuable tool to expand the pool of transplantable organs. However, the application of NMP to kidneys presents substantial challenges, mostly due to high variability in the composition of currently used perfusion solutions. Here, we provide a multimodal cross-species cellular atlas of kidney injury associated with NMP using a literature-based consensus buffer. This resource provided a systematic framework that was used to develop a metabolite-enhanced perfusion solution, which protected renal proximal tubular cells, improving cellular viability and transplantation outcomes across species, including human kidneys.

Authors

Jan Czogalla, Fabian Hausmann, Simon Lagies, Sydney E. Gies, Sabrina Christiansen, Nico Kaiser, Fabian Haas, Yusuke Okabayashi, Dominik Kylies, Smilla Hofmann, Rossana Franzin, Niklas Sabra, Sarah Bouari, Yitian Fang, Gisela Ambagtsheer, Ilka Edenhofer, Silvia Chilla, Anne K. Mühlig, Marina Zimmermann, Milagros N. Wong, Takashi Yokoo, Oliver Kretz, Maja Lindenmeyer, Florian Grahammer, Martin J. Hoogduijn, Ron de Bruin, Malte Kuehl, Sonja Hänzelmann, Bernd Kammerer, Loreto Gesualdo, Stefan Bonn, Robert C. Minnee, Tobias B. Huber, Victor G. Puelles

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Figure 5

Metabolic reprogramming with citric acid cycle metabolites improves kidney viability after NMP.

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Metabolic reprogramming with citric acid cycle metabolites improves kidn...
(A) We hypothesized that replenishment of the citric acid cycle intermediates lost during NMP would lead to improved mitochondrial health, leading to better tissue integrity. (B) We named the buffer containing these additions MEPS. (C) Mapping of downregulated metabolites onto the citric acid cycle showed both input- and output of the cycle were downregulated. Therefore, we replenished the main input and output metabolites of the citric acid cycle to generate MEPS. (D) MEPS was tested during mouse NMP. (E) Metabolomics of kidneys after perfusion with MEPS showed 17 significantly upregulated metabolites. Multiple unpaired t test was used for analysis of significance. (F) Main upregulated metabolites were closely related to mitochondrial processes. (G) Metabolite organelle mapping returned mitochondria as the sole organelle predicted to be improved by MEPS. Multiple unpaired t tests were used for statistical analysis. (H) Pathway analysis showed partial reversal of deleterious changes seen with consensus buffer.