Kidney tissue proteome profiles discriminate between short and long duration of delayed graft function in donation after circulatory death donors

Delayed graft function (DGF) is commonly defined as dialysis in the first week post-transplant. This definition, though readily applicable, is too generic and unable to distinguish between “types� of DGF or time needed to recover function. We aimed to profile biological pathways in DCD kidney donors that correlate with DGF and discriminate different durations. N=30 DCD kidney biopsies were selected from the UK Quality in Organ Donation biobank and stratified according to DGF duration (immediate function, IF n=10; “short-DGF� (1-6 days), SDGF n=10; “long-DGF� (7-22 days), LDGF n=10). Samples were matched for donor and recipient demographics and analysed by label-free quantitative proteomics, yielding identification of N=3,378 proteins. Ingenuity Pathway Analysis on differentially abundant proteins showed that SDGF kidneys presented stress response pathways upregulation, while LDGF presented impaired response to stress, compared to IF. LDGF showed extensive metabolic deficits compared to IF and SDGF. DCD kidneys requiring dialysis only in the first week post-transplant present acute cellular injury at donation, alongside repair pathways upregulation. In contrast, DCD kidneys requiring dialysis longer beyond 7 days present minimal metabolic and antioxidant responses, suggesting current DGF definitions might not be adequate in distinguishing different types of injury in the donor kidneys contributing to DGF.

移植肾功能延迟恢复（Delayed Graft Function, DGF）通常被定义为器官移植术后第一周内需要接受透析治疗。该定义虽易于落地实施，但过于笼统，无法区分DGF的不同‘类型’，也无法明确肾功能恢复所需的时长。本研究旨在分析循环死亡后捐献（Donation after Circulatory Death, DCD）肾脏供体的生物学通路，这些通路与DGF发生相关，且可区分不同的恢复时长。我们从英国器官捐献质量生物样本库中选取了30例DCD肾脏活检样本，并根据DGF持续时长进行分层：即刻肾功能恢复组（Immediate Function, IF, n=10）、短程DGF组（"short-DGF", 1~6天, n=10）以及长程DGF组（"long-DGF", 7~22天, n=10）。所有样本在供体与受体的人口统计学特征上进行了匹配，并通过无标记定量蛋白质组学（label-free quantitative proteomics）进行分析，最终鉴定出3378种蛋白质。对差异丰度蛋白进行Ingenuity通路分析（Ingenuity Pathway Analysis）结果显示，与IF组相比，SDGF组肾脏呈现应激反应通路的上调，而LDGF组则表现出应激应答受损；与IF组和SDGF组相比，LDGF组存在广泛的代谢功能缺陷。仅在移植术后第一周需要透析的DCD肾脏，在供体获取时即存在急性细胞损伤，同时伴随修复通路的上调。与之相反，移植术后透析时长超过7天的DCD肾脏仅表现出极微弱的代谢与抗氧化应答，这提示当前的DGF定义可能不足以区分供体肾脏中导致DGF的不同损伤类型。