Normothermic human kidney preservation drives iron accumulation and ferroptosis

Marlon J. A. Haan, Marleen E. Jacobs, Annemarie M. A. Graaf, Roan H. Scheppingen, Rico J. E. Derks, Dorottya K. Vries, Jesper Kers, Ian P. J. Alwayn, Cees Kooten, Elena Sánchez-López, Martin Giera, Marten A. Engelse and Ton J. Rabelink ()
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Marlon J. A. Haan: Leiden University Medical Center
Marleen E. Jacobs: Leiden University Medical Center
Annemarie M. A. Graaf: Leiden University Medical Center
Roan H. Scheppingen: Leiden University Medical Center
Rico J. E. Derks: Leiden University Medical Center
Dorottya K. Vries: Leiden University Medical Center
Jesper Kers: Leiden University Medical Center
Ian P. J. Alwayn: Leiden University Medical Center
Cees Kooten: Leiden University Medical Center
Elena Sánchez-López: Leiden University Medical Center
Martin Giera: Leiden University Medical Center
Marten A. Engelse: Leiden University Medical Center
Ton J. Rabelink: Leiden University Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61058-9

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