*Purpose: At present, a definitive diagnosis of organ dysfunction after transplantation (such as acute rejection) is dependent on conventional histopathological evaluation using an invasive biopsy procedure because blood tests and imaging results cannot conclusively diagnose such conditions. Recently, the usefulness of a liquid biopsy had been highlighted. This technique involves a minimally-invasive approach to collect samples, such as saliva, urine, or blood, which can be evaluated frequently without over-burdening the patient. Metabolomics is an omics technology that enables simultaneous identification and quantifications of hundreds of metabolites. This method has been employed to find these biomarker discoveries using biofluid samples. Here, we utilized metabolomics technologies to discover new biomarkers of acute kidney rejection after transplantation.

*Methods: Patients who underwent kidney transplantation were followed-up at our hospital and grouped into three groups as follows: kidney transplant donors (healthy subjects, n=9), subjects with normal kidney function after kidney transplantation (n=19), and subjects with impaired kidney function after kidney transplantation (n=32). Pathological diagnosis of this group included T cell-mediated acute rejection (AR) (n=10), antibody-mediated rejection (n=8), calcineurin inhibitor nephropathy (n=3), and the other causes of graft function (n=8). Metabolome analysis was performed on 60 blood, urine, and saliva specimens from the subjects. The results of the metabolome analysis were compared with the definitive diagnoses determined using kidney graft biopsy.

*Results: In the group of subjects with impaired kidney function after kidney transplantation, eight substances in blood (asymmetrical dimethylarginine [ADMA], diethanolamine, glycerophosphorylcholine, isocitrate, phenylalanine, symmetrical dimethylarginine [SDMA], serotonin, and valine), three substances in urine (3-indoxy sulfate, ADMA, and N-acetylhistidine), and seven substances in saliva (2-hydroxyglutarate, adipate, ethanolamine phosphate, fumalate, glycolate, proline, sedoheptulose 7-phosphate) were significantly different (p<0.001) from those among the three groups.

*Conclusions: The salivary test has significant advantages compared to the blood-based test, which can be performed frequently due to its non-invasiveness. Such AR diagnosis methods would be useful as a clinical application.

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