A cross-sectional study of the role of epithelial cell injury in kidney transplant outcomes.
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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
Аннотация
METHODS: We defined injury-induced transcriptome states in 4,502 kidney transplant biopsies injury-induced gene sets and classifiers previously developed in transplants.
RESULTS: 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.
CONCLUSION: 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.
TRIAL REGISTRATION: INTERCOMEX (ClinicalTrials.gov NCT01299168); Trifecta-Kidney (ClinicalTrials.gov NCT04239703).
FUNDING: Genome Canada; Natera, Inc.; and Thermo Fisher Scientific.