Peripheral transcriptomic signature of chronic antibody-mediated rejection in kidney transplantation: a dual effect for MMP9 over time

BACKGROUNDChronic antibody-mediated rejection (CAMR) is the main cause of late kidney allograft loss, and no specific effective treatment has been identified so far. Here, we proposed to explore the non-invasive peripheral blood transcriptome signature of CAMR. METHODSFirst, we compared PBMC gene expression from bulk RNA-seq between 35 patients experiencing late CAMR (mean=7.1 years) vs. 43 patients without graft dysfunction at late stages (Stable, mean=4.4 years) to identify the molecular drivers of CAMR. Second, we explored the 1-year gene expression signature in stable patients exhibiting (n=11) or not (n=51) a subsequent CAMR to define possible predictive biomarkers of CAMR. RESULTSWe reported 188 differentially regulated genes during late CAMR (q<0.05). Importantly, CAMR is associated with an upregulation of genes from the degranulation pathway (e.g. MMP9, MMP8 and LCN2) and from the C1q complement complex (e.g. C1QA, C1QB and C1QC), as well as with a downregulation of genes associated with subclinical rejection (e.g. TCL1A). The upregulated degranulation and complement signatures were validated in six independent cohorts gathering a total of 360 stable and 131 chronic rejection patients. Contrary to the injury effect observed during late stages, MMP9 was downregulated at 1-year in PBMCs of patients who later experienced CAMR. CONCLUSIONSThese results suggest a dual role for MMP9 expression with an early protective effect against CAMR and deleterious effects in the later stage. MMP9 peripheral expression appears as a promising biomarker candidate for kidney transplantation follow-up. Translational StatementCAMR is the main cause of late kidney allograft loss, and we aimed to identify molecular targets and biomarkers. By comparing CAMR and stable kidney-transplanted patients prior and during diagnosis, we identified MMP9 as a potential biomarker for both CAMR prognosis and diagnosis. We also highlighted the C1q complement complex and TCL1A in CAMR as potential diagnostic biomarkers. These results provide new insights into CAMR pathophysiology and may guide the development of innovative treatment targeting MMP9 expression in kidney transplanted patients. Ultimately, this work laid the foundation for exploring MMP9 expression kinetics and develop new ways of treating CAMR patients.