Normothermic human kidney preservation drives iron accumulation and ferroptosis
Abstract Ex vivo normothermic machine perfusion has been proposed to protect deceased donor kidneys. However, its benefits remain ambiguous. We postulate that the use of red blood cells (RBCs) and associated secondary hemolysis may in fact cause renal injury, offsetting potential advantages. During...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61058-9 |
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| author | Marlon J. A. de Haan Marleen E. Jacobs Annemarie M. A. de Graaf Roan H. van Scheppingen Rico J. E. Derks Dorottya K. de Vries Jesper Kers Ian P. J. Alwayn Cees van Kooten Elena Sánchez-López Martin Giera Marten A. Engelse Ton J. Rabelink |
| author_facet | Marlon J. A. de Haan Marleen E. Jacobs Annemarie M. A. de Graaf Roan H. van Scheppingen Rico J. E. Derks Dorottya K. de Vries Jesper Kers Ian P. J. Alwayn Cees van Kooten Elena Sánchez-López Martin Giera Marten A. Engelse Ton J. Rabelink |
| author_sort | Marlon J. A. de Haan |
| collection | DOAJ |
| description | Abstract Ex vivo normothermic machine perfusion has been proposed to protect deceased donor kidneys. However, its benefits remain ambiguous. We postulate that the use of red blood cells (RBCs) and associated secondary hemolysis may in fact cause renal injury, offsetting potential advantages. During 48-hour normothermic perfusion of seven human donor kidneys, we observed progressive hemolysis, leading to iron accumulation in perfusate and tissue. Untargeted lipidomic profiling revealed significant increases in oxidized phospholipid species in perfused kidneys, pointing towards iron-dependent cell death known as ferroptosis. Next, in twelve additional perfusions, we assessed strategies to mitigate hemolysis-driven injury. Dialysis-based free hemoglobin removal reduced lipid peroxidation, but a ferroptosis gene signature persisted. In contrast, cell-free perfusion at subnormothermia negated iron accumulation, the ferroptosis gene signature, phospholipid peroxidation, and acute kidney injury. Our findings highlight the pathological role of hemolysis and iron on the kidney, urging restraint in the clinical application of RBC-based kidney perfusion. |
| format | Article |
| id | doaj-art-4acb5e42eb1a47778ea76e31392fe283 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-4acb5e42eb1a47778ea76e31392fe2832025-08-20T04:01:35ZengNature PortfolioNature Communications2041-17232025-07-0116111310.1038/s41467-025-61058-9Normothermic human kidney preservation drives iron accumulation and ferroptosisMarlon J. A. de Haan0Marleen E. Jacobs1Annemarie M. A. de Graaf2Roan H. van Scheppingen3Rico J. E. Derks4Dorottya K. de Vries5Jesper Kers6Ian P. J. Alwayn7Cees van Kooten8Elena Sánchez-López9Martin Giera10Marten A. Engelse11Ton J. Rabelink12Department of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical CenterDepartment of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical CenterDepartment of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical CenterDepartment of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical CenterCenter of Proteomics and Metabolomics, Leiden University Medical CenterTransplant Center, Leiden University Medical CenterTransplant Center, Leiden University Medical CenterTransplant Center, Leiden University Medical CenterDepartment of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical CenterThe Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical CenterThe Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical CenterDepartment of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical CenterDepartment of Internal Medicine (Nephrology) & Einthoven Laboratory of Vascular and Regenerative Medicine, Leiden University Medical CenterAbstract Ex vivo normothermic machine perfusion has been proposed to protect deceased donor kidneys. However, its benefits remain ambiguous. We postulate that the use of red blood cells (RBCs) and associated secondary hemolysis may in fact cause renal injury, offsetting potential advantages. During 48-hour normothermic perfusion of seven human donor kidneys, we observed progressive hemolysis, leading to iron accumulation in perfusate and tissue. Untargeted lipidomic profiling revealed significant increases in oxidized phospholipid species in perfused kidneys, pointing towards iron-dependent cell death known as ferroptosis. Next, in twelve additional perfusions, we assessed strategies to mitigate hemolysis-driven injury. Dialysis-based free hemoglobin removal reduced lipid peroxidation, but a ferroptosis gene signature persisted. In contrast, cell-free perfusion at subnormothermia negated iron accumulation, the ferroptosis gene signature, phospholipid peroxidation, and acute kidney injury. Our findings highlight the pathological role of hemolysis and iron on the kidney, urging restraint in the clinical application of RBC-based kidney perfusion.https://doi.org/10.1038/s41467-025-61058-9 |
| spellingShingle | Marlon J. A. de Haan Marleen E. Jacobs Annemarie M. A. de Graaf Roan H. van Scheppingen Rico J. E. Derks Dorottya K. de Vries Jesper Kers Ian P. J. Alwayn Cees van Kooten Elena Sánchez-López Martin Giera Marten A. Engelse Ton J. Rabelink Normothermic human kidney preservation drives iron accumulation and ferroptosis Nature Communications |
| title | Normothermic human kidney preservation drives iron accumulation and ferroptosis |
| title_full | Normothermic human kidney preservation drives iron accumulation and ferroptosis |
| title_fullStr | Normothermic human kidney preservation drives iron accumulation and ferroptosis |
| title_full_unstemmed | Normothermic human kidney preservation drives iron accumulation and ferroptosis |
| title_short | Normothermic human kidney preservation drives iron accumulation and ferroptosis |
| title_sort | normothermic human kidney preservation drives iron accumulation and ferroptosis |
| url | https://doi.org/10.1038/s41467-025-61058-9 |
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