INTRODUCTION: Chronic antibody-mediated rejection (CAMR) is currently the leading cause of long-term allograft loss, affecting approximately 50-60% of renal transplant recipients after a decade. Although in the last years many studies have performed to define clinical/histological characteristics and to identify the leading causes and triggers of this condition, at the moment, the complete biological machinery associated with this complex complication has been only partially defined. METHODS: We performed mass-spectrometry-based serum proteomics of 19 patients with CAMR and 26 kidney transplant recipients without any functional alteration (CTR). The results were compared with a previously obtained transcriptomic profile of peripheral blood mononuclear cells (PBMC) isolated from 10 CAMR and 8 CTR. The biological elements identified by the statistical analysis were then validated through ELISA in all patients. RESULTS: Proteomics demonstrated that 18 proteins were able to discriminate CAMR from CTR (p<0.01): five proteins resulted 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) in CAMR compared with CTR patients. The innovative bioinformatic analysis (SVM, PLS-DA) applied to transcriptomic data revealed that 6 genes were down-regulated, and 33 genes were up-regulated in CAMR compared with CTR patients (p<0.01). Notably, only 2 biological elements resulted significantly deregulated in both omics analyses: chitinase-3-like protein 1 (CHI3L1) and plasma protease inhibitor C1 (SERPING1). CHI3L1 was up-regulated in CAMR in both transcriptomics and proteomics, while SERPING1 was up-regulated in CAMR in transcriptomics, but down-regulated in proteomics. ELISA validated the omics data and ROC curve indicated that CHI3L1 had good discrimination power between CAMR and CTR. CONCLUSIONS: The results of the multi-omics analysis confirmed the evident systemic immunological perturbation of patients with CAMR and identified CHI3L1 as a new potential biomarker and therapeutic target for this important clinical complication.