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Molecular Fingerprints of Borderline Changes of Kidney Allografts is Influenced by Donor Category

ABSTRACT: The fate of transplanted kidneys is substantially influenced by the graft quality as transplantation of kidneys from elderly and expanded criteria deceased donors (ECD) is associated with higher occurrence of delayed graft function, rejection and inferior long term outcome. Little is known about early molecular fingerprints of these events in different donor categories. Borderline changes represent the most frequent histological finding early after kidney transplantation. Therefore, transcriptomic profiles of early case biopsies diagnosed as borderline changes were studied in ECD, standard criteria deceased donors (SCD) and living donor (LD) kidney transplantation using RNA microarray (Agilent SurePrintG3). The increased transcripts typical for ECD as compared to LD (n=437) showed enrichment of extracellular matrix (ECM) -receptor interaction (p=0.004) and complement and coagulation pathways (p=0.004) and GO terms related to platelet activation, blood coagulation, regulation of cell cycle, acute inflammatory response, wound healing or defense response (p<0.001). Gene annotation analysis of transcripts with increased expression in ECD grafts compared to SCD (n=244) showed the highest enrichment of inflammatory response (p=0.013), response to wounding (p=0.001) and defense response (p=0.005) and ECM-receptor interaction pathway (p=0.043). Comparative gene expression overlaps of ECD, SCD and LD using Venn’s diagrams found 62 up- and 16 down-regulated genes in ECD compared to both LD and SCD. Shared increased transcripts in ECD vs. both SCD and LD included, thrombospondin 2 (THBS2), angiopoietin-like 4 (ANGPTL4), collagens (COL6A3, COL1A1), chemokines CCL13 or interleukin IL11 and most significant down-regulated transcripts included proline rich 35 (PRR35) and fibroblast growth factor 9 (FGF9). Transcriptomic profile of higher inflammation and extracellular matrix remodeling in early borderline changes in the ECD kidney allografts suggest mechanisms how ischemia/reperfusion injury aggravates alloimmune response in the presence of chronic vascular changes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE134386 | GEO | 2019/07/18

REPOSITORIES: GEO

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Project description:The survival of transplant kidneys using deceased donors (DD) is inferior to living donors (LD). In this study, we conducted a whole-transcriptome expression analysis of 24 human kidney biopsies paired 30 minutes and 3 months post-transplantation using DD and LD. The transcriptome profile was found significantly different between two time points regardless of donor types. There were 446 differentially expressed genes (DEGs) between DD and LD at 30 minutes and 146 DEGs at 3 months, with 25 genes common to both time points. These DEGs reflected donor injury and acute immune responses associated with inflammation and cell death as early as at 30 minutes, which could be a precious window of potential intervention. DEGs at 3 months mainly represented the changes of adaptive immunity, immunosuppressive treatment, remodeling or fibrosis via different networks and signaling pathways. The expression level of 20 DEGs involved in kidney diseases, and 10 genes found dysregulated at 30 minutes were validated by quantitative PCR (qPCR) in the 24 samples analyzed by microarray as well as in a validation cohort of 33 unpaired allograft biopsies. Their expression levels were found correlated with renal function and histology at 12 months, suggesting they could be potential biomarkers to predict kidney function. This analysis revealed that SERPINA3, SLPI and CBF is upregulated at 30 minutes in DD compared to LD, whereas FTCD and TASPN7 are up-regulated at both time points; at 3 months VCAN and TIMP1 are up-regulated, whereas FOS is decreased in both donors. Taken together, divergent transcriptomic signatures between DD and LD, and changed by the time post-transplantation, might contribute to different allograft survival of two type kidney donors. Some DEGs such as FTCD and TASPN7 could be novel biomarkers not only for timely diagnosis, but also early for precise genetic intervention at donor preservation, implantation and post-transplantation, in particular to effectively improve the quality and survival of DD.

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Molecular Fingerprints of Borderline Changes of Kidney Allografts is Influenced by Donor Category

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