Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK.
Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK; Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Kidney Int. 2024 Aug;106(2):302-316. doi: 10.1016/j.kint.2024.03.028. Epub 2024 Apr 29.
Organ shortage is a major challenge in kidney transplantation but the use of older donors, often with co-morbidities, is hampered by inconsistent outcomes. Methods of accurately stratifying marginal donor organs by clinical and histological assessment are lacking. To better understand organ variability, we profiled the transcriptomes of 271 kidneys from deceased donors at retrieval. Following correction for biopsy composition, we assessed molecular pathways that associated with delayed, and sub-optimal one-year graft function. Analysis of cortical biopsies identified an adaptive immune gene-rich module that significantly associated with increasing age and worse outcomes. Cellular deconvolution using human kidney reference single cell transcriptomes confirmed an increase in kidney-specific B and T cell signatures, as well as kidney macrophage, myofibroblast and fibroblast gene sets in this module. Surprisingly, innate immune pathway and neutrophil gene signature enrichment was associated with better outcomes. Thus, our work uncovers cellular molecular features of pathological organ ageing, identifiable at kidney retrieval, with translational potential.
器官短缺是肾移植的一个主要挑战，但由于结果不一致，使用伴有合并症的老年供体受到阻碍。目前缺乏通过临床和组织学评估准确分层边缘供体器官的方法。为了更好地了解器官的变异性，我们对 271 个来自死亡供体的肾脏进行了转录组分析。在对活检组成进行校正后，我们评估了与延迟和亚最佳一年移植物功能相关的分子途径。对皮质活检的分析确定了一个适应性免疫基因丰富的模块，该模块与年龄增加和预后不良显著相关。使用人类肾脏参考单细胞转录组进行的细胞去卷积证实，该模块中肾脏特异性 B 和 T 细胞标志物以及肾脏巨噬细胞、肌成纤维细胞和成纤维细胞基因集增加。令人惊讶的是，固有免疫途径和中性粒细胞基因特征的富集与更好的结果相关。因此，我们的工作揭示了可在肾脏获取时识别的病理性器官老化的细胞分子特征，具有转化潜力。
