Urinary metabolomic profiling from spontaneous tolerant kidney transplanted recipients shows enrichment in tryptophan-derived metabolites

Background Operational tolerance is the holy grail in solid organ transplantation. Previous reports showed that the urinary compartment of operationally tolerant recipients harbor 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. Supervised and unsupervised multivariate computational analyses were used to highlight urinary metabolomic profile and metabolite identification thanks to workflow4metabolomic platform. Findings The urinary metabolome was composed of approximately 2700 metabolites. Raw unsupervised clustering allowed us to separate healthy volunteers and tolerant KTR from others. We confirmed by two methods a specific urinary metabolomic signature in tolerant KTR mainly driven by kynurenic acid independent of immunosuppressive drugs, serum creatinine and gender. Interpretation Kynurenic acid and tryptamine enrichment allowed the identification of putative pathways and metabolites associated with operational tolerance like IDO, GRP35 and AhR and indole alkaloids. Funding This study was supported by the ANR, IRSRPL and CHU de Nantes.