Halloran Philip F, Chang Jessica, Mackova Martina, Madill-Thomsen Katelynn S, Akalin Enver, Alhamad Tarek, Anand Sanjiv, Arnol Miha, Baliga Rajendra, Banasik Mirosław, Blosser Christopher D, Böhmig Georg, Brennan Daniel, Bromberg Jonathan, Budde Klemens, Chamienia Andrzej, Chow Kevin, Ciszek Michał, de Freitas Declan, Dęborska-Materkowska Dominika, Debska-Ślizień Alicja, Djamali Arjang, Domański Leszek, Durlik Magdalena, Einecke Gunilla, Eskandary Farsad, Fatica Richard, Francis Iman, Fryc Justyna, Gill John, Gill Jagbir, Glyda Maciej, Gourishankar Sita, Gryczman Marta, Gupta Gaurav, Hruba Petra, Hughes Peter, Jittirat Arskarapurk, Jurekovic Zeljka, Kamal Layla, Kamel Mahmoud, Kant Sam, Kojc Nika, Konopa Joanna, Lan James, Mannon Roslyn B, Matas Arthur, Mazurkiewicz Joanna, Miglinas Marius, Mueller Thomas, Myślak Marek, Narins Seth, Naumnik Beata, Patel Anita, Perkowska-Ptasińska Agnieszka, Picton Michael, Piecha Grzegorz, Poggio Emilio, Rajnochová Bloudíčkova Silvie, Schachtner Thomas, Shojai Soroush, Sikosana Majid Ln, Slatinská Janka, Smykal-Jankowiak Katarzyna, Solanki Ashish, Veceric Haler Željka, Viklicky Ondrej, Vucur Ksenija, Weir Matthew R, Wiecek Andrzej, Włodarczyk Zbigniew, Yang Harold, Zaky Ziad, Gauthier Patrick T, Hinze Christian
Alberta Transplant Applied Genomics Centre and.
University of Alberta, Edmonton, Alberta, Canada.
JCI Insight. 2025 Apr 15;10(10). doi: 10.1172/jci.insight.188658. eCollection 2025 May 22.
Expression of acute kidney injury-associated (AKI-associated) transcripts in kidney transplants may reflect recent injury and accumulation of epithelial cells in "failed repair" states. We hypothesized that the phenomenon of failed repair could be associated with deterioration and failure in kidney transplants.
We defined injury-induced transcriptome states in 4,502 kidney transplant biopsies injury-induced gene sets and classifiers previously developed in transplants.
In principal component analysis (PCA), PC1 correlated with both acute and chronic kidney injury and related inflammation and PC2 with time posttransplant. Positive PC3 was a dimension that correlated with epithelial remodeling pathways and anticorrelated with inflammation. Both PC1 and PC3 correlated with reduced survival, with PC1 effects strongly increasing over time whereas PC3 effects were independent of time. In this model, we studied the expression of 12 "new" gene sets annotated in single-nucleus RNA-sequencing studies of epithelial cells with failed repair in native kidneys. The new gene sets reflecting epithelial-mesenchymal transition correlated with injury PC1 and PC3, lower estimated glomerular filtration rate, higher donor age, and future failure as strongly as any gene sets previously derived in transplants and were independent of nephron segment of origin and graft rejection.
These results suggest 2 dimensions in the kidney transplant response to injury: PC1, AKI-induced changes, failed repair, and inflammation; and PC3, a response involving epithelial remodeling without inflammation. Increasing kidney age amplifies PC1 and PC3.
INTERCOMEX (ClinicalTrials.gov NCT01299168); Trifecta-Kidney (ClinicalTrials.gov NCT04239703).
Genome Canada; Natera, Inc.; and Thermo Fisher Scientific.
肾移植中急性肾损伤相关（AKI相关）转录本的表达可能反映近期损伤以及处于“修复失败”状态的上皮细胞的积累。我们推测修复失败现象可能与肾移植的恶化和功能衰竭有关。
我们在4502份肾移植活检样本中定义了损伤诱导的转录组状态，这些样本使用了先前在移植中开发的损伤诱导基因集和分类器。
在主成分分析（PCA）中，PC1与急性和慢性肾损伤以及相关炎症相关，PC2与移植后时间相关。正向PC3是一个与上皮重塑途径相关且与炎症呈负相关的维度。PC1和PC3均与生存率降低相关，PC1的影响随时间强烈增加，而PC3的影响与时间无关。在该模型中，我们研究了在天然肾脏中修复失败的上皮细胞的单核RNA测序研究中注释的12个“新”基因集的表达。反映上皮-间质转化的新基因集与损伤PC1和PC3、较低的估计肾小球滤过率、较高的供体年龄以及未来的功能衰竭相关，其关联强度与先前在移植中得出的任何基因集一样强，并且独立于起源的肾单位节段和移植排斥反应。
这些结果表明肾移植对损伤的反应存在两个维度：PC1，AKI诱导的变化、修复失败和炎症；以及PC3，一种涉及无炎症的上皮重塑的反应。肾龄增加会放大PC1和PC3。
INTERCOMEX（ClinicalTrials.gov NCT01299168）；Trifecta-Kidney（ClinicalTrials.gov NCT04239703）。
加拿大基因组公司；Natera公司；以及赛默飞世尔科技公司。
Zotero 插件
