#887 The multi-omic analysis identified CHI3L1 as a potential mediator of immune system deregulation in kidney transplant patients with chronic antibody-mediated rejection

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Abstract Background and Aims Chronic antibody-mediated rejection (CAMR) is the leading cause of functional loss in kidney transplantation and, in many cases, despite appropriate treatment, does not respond to current therapies. Therefore, there is a need to identify new biological factors to improve early diagnosis or potential therapeutic targets. To achieve these goals, molecular biology and multi-omics methodologies can prove to be very useful tools. Methods We compared mass spectrometry-based proteomic profiling of serum samples from 19 patients with CAMR and 26 kidney transplant recipients with normal graft function and histology (CTR) and the transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from an independent cohort of 10 CAMR and 8 CTR patients. Data analysis was conducted using unsupervised hierarchical clustering (multidimensional scaling with k-means) and Spearman's correlation test. Partial least squares discriminant analysis (PLS-DA) with k-means and variable importance in projection (VIP) score identified key proteins differentiating CAMR from CTR. ELISA was used to validate omics results. Results The bioinformatics analysis combined with functional analysis (Gene Ontology), demonstrated that 18 proteins significantly differentiated CAMR from CTR (P < 0.01): five were more abundant (CHI3L1, LYZ, PRSS2, CPQ, IGLV3-32), while 13 were less abundant (SERPINA5, SERPING1, KNG1, CAMP, VNN1, BTD, WDR1, PON3, AHNAK2, MELTF, CA1, CD44, CUL1). Transcriptomic profiling revealed 6 downregulated and 33 upregulated genes in CAMR versus CTR (P < 0.01). The overlapping analysis identified chitinase-3-like protein 1 (CHI3L1), a protein previously associated with the severity of tissue damage in kidney diseases, as the most significant biological factor simultaneously overexpressed in CAMR patients in both transcriptomics and proteomics. ELISA validated the omics data and CHI3L1 reached good discrimination power for CAMR identification (AUC of ROC curve of 0.81). Conclusions The results of the multi-omics analysis confirmed the deregulation of immune system in CAMR patients and identified CHI3L1 as a new potential biomarker and therapeutic target for this significant clinical complication.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.