Abstract
Acute rejection (AR) is closely associated with renal allograft dysfunction. Here, we utilised RNA sequencing (RNA-Seq) and bioinformatic methods to characterise the peripheral blood mononuclear cells (PBMCs) of patients with acute renal allograft rejection. Pretransplant blood samples were collected from 32 kidney allograft donors and 42 corresponding recipients with biopsies classified as T cell-mediated rejection (TCMR, n = 18), antibody-mediated rejection (ABMR, n = 5), and normal/non-specific changes (non-AR, n = 19). The patients with TCMR and ABMR were assigned to the AR group, and the patients with normal/non-specific changes (n = 19) were assigned to the non-AR group. We analysed RNA-Seq data for identifying differentially expressed genes (DEGs), and then gene ontology (GO) analysis, Reactome, and ingenuity pathway analysis (IPA), protein—protein interaction (PPI) network, and cell-type enrichment analysis were utilised for bioinformatics analysis. We identified DEGs in the PBMCs of the non-AR group when compared with the AR, ABMR, and TCMR groups. Pathway and GO analysis showed significant inflammatory responses, complement activation, interleukin-10 (IL-10) signalling pathways, classical antibody-mediated complement activation pathways, etc., which were significantly enriched in the DEGs. PPI analysis showed that IL-10, VEGFA, CXCL8, MMP9, and several histone-related genes were the hub genes with the highest degree scores. Moreover, IPA analysis showed that several proinflammatory pathways were upregulated, whereas antiinflammatory pathways were downregulated. The combination of NFSF14+TANK+ANKRD 33 B +HSPA1B was able to discriminate between AR and non-AR with an AUC of 92.3% (95% CI 82.8–100). Characterisation of PBMCs by RNA-Seq and bioinformatics analysis demonstrated gene signatures and biological pathways associated with AR. Our study may provide the foundation for the discovery of biomarkers and an in-depth understanding of acute renal allograft rejection.
Highlights
Kidney transplantation is the optimal choice for patients with end-stage renal disease (ESRD)
We performed RNA sequencing (RNA-Seq) on 74 pretransplant blood peripheral blood mononuclear cells (PBMCs) samples collected from 32 kidney allograft donors and 42 corresponding recipients, whose kidney biopsies were classified as Acute rejection (AR), including and 5 patients with T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR), respectively, and patients with non-AR
A study revealed that mRNAs for four chemokines (CCL5, CXCL9, CXCL10, and CXCL11) were positively enriched in TCMR urine compared with non-rejection urine
Summary
Kidney transplantation is the optimal choice for patients with end-stage renal disease (ESRD). Acute rejection (AR) cannot be avoided when transplanting tissue or cells from a genetically different donor to the graft recipient because the alloantigen of the donor induces an immune response against the graft in the recipient [1]. Acute rejection can occur at any time following transplantation, usually within days to weeks. It is classified as antibody-mediated rejection (ABMR) or acute T cell-mediated rejection (TCMR). AR occurs in approximately 10–20% of cases; significant improvement in long-term allograft survival rates remains unrealised [2–4]. It has been reported that graft failures occur if AR occurs, even after immunosuppressive treatment, and each episode of rejection is closely associated with a poor graft survival rate [5, 6]
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