BACKGROUND: 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. 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.

Alberta Transplant Applied Genomics Centre and

Charité Universitätsmedizin Berlin Berlin Germany

Cleveland Clinic Foundation Cleveland Ohio USA

Hannover Medical School Hannover Germany

Henry Ford Transplant Institute Detroit Michigan USA

Institute for Experimental and Clinical Medicine Prague Czech Republic

Intermountain Transplant Services Murray Utah USA

Johns Hopkins University School of Medicine Baltimore Maryland USA

Manchester Royal Infirmary Manchester United Kingdom

Medical University of Białystok Białystok Poland

Medical University of Gdańsk Gdańsk Poland

Medical University of Vienna Vienna Austria

Medical University of Wrocław Wrocław Poland

Montefiore Medical Center Bronx New York USA

PinnacleHealth Transplant Associates UPMC Harrisburg Pennsylvania USA

Pomeranian Medical University Szczecin Poland

Silesian Medical University Katowice Poland

St Paul's Hospital Vancouver British Columbia Canada

Tampa General Hospital Tampa Florida USA

The Royal Melbourne Hospital Parkville Victoria Australia

University Hospital Cleveland Medical Center Cleveland Ohio USA

University Hospital Merkur Zagreb Croatia

University Hospital No 1 Bydgoszcz Poland

University Hospital Zurich Zurich Switzerland

University of Alabama at Birmingham Birmingham Alabama USA

University of Alberta Edmonton Alberta Canada

University of Ljubljana Ljubljana Slovenia

University of Maryland Baltimore Maryland USA

University of Minnesota Minneapolis Minnesota USA

University of Washington Seattle Washington USA

University of Wisconsin Madison Wisconsin USA

Vilnius University Hospital Santaros Klinikos Vilnius Lithuania

Virginia Commonwealth University Richmond Virginia USA

Warsaw Medical University Warsaw Poland

Washington University at St Louis St Louis Missouri USA

Wojewodzki Hospital Poznan Poland

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ClinicalTrials.gov
NCT04239703, NCT01299168