*Purpose: Operational tolerance is the holy grail in solid organ transplantation. Previous reports showed that the urinary compartment of operationally tolerant recipients harbored a specific and unique profile. We hypothesized that spontaneous tolerant kidney transplanted recipients (KTR) would have a specific urinary metabolomic profile associated to operational tolerance.

*Methods: We performed metabolomic profiling on urine samples from healthy volunteers, stable KTR under standard and minimal immunosuppression and spontaneous tolerant KTR using liquid chromatography in tandem with mass spectrometry (UHPLC/MS). Supervised and unsupervised multivariate computational analyses were used to highlight urinary metabolomic profile and metabolite identification thanks to workflow4metabolomic platform.

*Results: The urinary metabolome was composed of approximately 2700 metabolites. Raw unsupervised clustering allowed us to separate healthy volunteers and tolerant KTR from others. For the first time, we identified a specific urinary metabolomic signature in tolerant KTR of twelve leading ions mainly driven by kynurenic acid independent of immunosuppressive drugs, serum creatinine and gender. Moreover, both kynurenine and tryptamine pathways were upregulated in tolerant KTR.

*Conclusions: Kynurenine pathway metabolites and tryptamine enrichment allowed the identification of putative pathways associated with spontaneous operational tolerance such as IDO, GRP35 and AhR signaling and microbiota-derived tryptophan metabolites such as indole alkaloids. Further studies on larger cohorts are then needed to better model the metabolomic network. In parallel, multiomic models (metabolomic and microbiomic) on several compartments (plasma, urine and kidney graft tissue if possible) coupled with in vitro/in vivo studies are mandatory to better decipher their potential roles in spontaneous operational tolerance in KTR.

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