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Local regulation and clinical impact of complement gene expression in deceased and living donor kidney allografts

ABSTRACT: The biopsy samples obtained at implantation segregated in 2 distinct groups according to donor origin, with a cluster of 319 unique identified genes higher expressed in DD compared to LD kidneys, and 329 genes lower expressed (false discovery rate <5%). Using pathway analysis software a significant local renal overrepresentation of complement genes in DD implantation biopsies was identified. Complement gene expression in DD kidneys related both to donor death and cold ischemia duration, and was associated with a slower onset of renal allograft function. In post-transplantation protocol biopsies, there was a continued overexpression of complement genes, regardless of donor source. The local renal complement gene expression variability in post-transplantation biopsies correlated with renal graft function. This study demonstrates a significant and clinically relevant local overexpression of complement genes in DD kidneys at engraftment and continuous functionally important regulation of complement gene expression after transplantation, regardless of donor source. Targeted therapy interfering with complement activation is an attractive therapeutic target that deserves further investigation in solid organ transplantation. Keywords: time course, genomics gene expression

ORGANISM(S): Homo sapiens

PROVIDER: GSE11166 | GEO | 2008/04/16

SECONDARY ACCESSION(S): PRJNA106859

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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Local regulation and clinical impact of complement gene expression in deceased and living donor kidney allografts

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