Cellular Responses During Kidney Normothermic Machine Perfusion Reflect Graft Outcomes

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Introduction: Kidneys donated after circulatory death and kidneys from older donors demonstrate increased susceptibility to ischemia reperfusion injury and immune attack after transplantation. However, there are currently no assessment tools that can reliably predict posttransplant outcome of donor kidneys. In this study, we investigated whether the cellular responses of kidneys during normothermic machine perfusion (NMP) are associated with posttransplant outcome. Methods: Snap-frozen biopsies from 6 kidneys taken before and after 2-hour NMP were subjected to single nucleus RNA sequencing (snRNA seq). Biopsies from another 22 kidneys taken at the same time points were included for quantitative real-time PCR (qPCR) to confirm the snRNA seq data. Estimated glomerular filtration rates (eGFRs) until 30 days posttransplant were used to determine posttransplant function. Results: snRNA seq analyses of kidney biopsies identified 38,451 cells distributed across 11 distinct cell types. NMP induced an upregulation of genes for adenosine triphosphate (ATP) production-related proteins, heat shock proteins (HSPs), transporter proteins, and proteins that prevent protein misfolding. These findings were confirmed by the qPCR analyses. We observed no significant gene differences between delayed graft function (DGF) and non-DGF kidneys. However, after NMP, the expression of HSP was above average in 3 kidneys that experienced acute rejection in the first 10 days after transplantation compared with nonrejecting kidneys. Conclusion: This study demonstrates that 2-hour NMP impacts gene expression profiles of the majority of cell types of the kidney. It suggests that NMP triggers differential gene expression patterns in kidneys with an increased risk for early rejection.

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