Abstract
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 at 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 levels of 20 highly DEGs involved in kidney diseases and 10 genes dysregulated at 30 minutes were found correlated with renal function and histology at 12 months, suggesting they could be potential biomarkers. These genes were further validated by quantitative polymerase chain reaction (qPCR) in 24 samples analysed by microarray, as well as in a validation cohort of 33 time point unpaired allograft biopsies. This analysis revealed that SERPINA3, SLPI and CBF were up-regulated at 30 minutes in DD compared to LD, while FTCD and TASPN7 were up-regulated at both time points. At 3 months, SERPINA3 was up-regulated in LD, but down-regulated in DD, with increased VCAN and TIMP1, and decreased FOS, 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 including FTCD and TASPN7 could be novel biomarkers not only for timely diagnosis, but also for early precise genetic intervention at donor preservation, implantation and post-transplantation, in particular to effectively improve the quality and survival of DD.
Highlights
Kidney transplantation is a life-change treatment for end-stage renal failure patients
This study revealed divergent transcriptomic signatures between deceased donors (DD) and living donors (LD), changed by time post-transplantation, might contribute to the different survival of two type kidney allografts
Warm ischemic time was shorter, but cold ischemic time was longer in DD vs LD for 12 microarray analysis and 33 quantitative polymerase chain reaction (qPCR) validation patients (Tables 2A, B)
Summary
Kidney transplantation is a life-change treatment for end-stage renal failure patients. High throughput genomic technologies, such as microarray, enable investigating hundreds of thousands of genes in one sample at one time, and identifying differentially expressed genes (DEGs) involved in allograft/recipient survival. A meta-analysis using 150 microarray samples from ischemia-reperfusion (IR) kidneys identified DEGs, corrected the bias in models and species. 26 DEGs including LCN2, CCL2, HMOX1, ICAM1 and TIMP1 were associated with kidney transplantation injury [11]. An additional multicenter prospective study reported that 13 genes from 159 renal biopsies at 3 months post-transplantation with stable renal function could discriminate allografts at high or low risk of CAI before irreversible histological damage occurred at 12 months [13]. The ultimate goal of these studies is to identify and validate DEGs as potential biomarkers to predict and diagnose CAI and improve post-transplantation care
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