Perspective: metabolomics has the potential to change the landscape of kidney transplantation diagnostics

Kidney transplantation is the most efficient renal replacement therapy. Current diagnostics for monitoring graft health are either invasive or lack precision. Metabolomics is an emerging discipline focused on the analysis of the small molecules involved in metabolism. Given the kidneys' central role in metabolic homeostasis and previous observations of altered metabolites correlating with restricted kidney graft function, metabolomics is highly promising for the discovery of novel biomarkers and the development of novel diagnostics. In this perspective, we summarize the known metabolic roles for the kidney, discuss biomarkers of graft health and immune status emerging from metabolomics research, and provide our perspective on how these and future findings can be integrated in clinical practice to enable precision diagnostics. Kidney transplantation (KT) remains the best treatment for renal disease but better diagnostic tests for monitoring graft health are required as the current ones are inadequate. Metabolomics, the study of small molecule metabolites in biological samples, is poised to enable the discovery of novel metabolite biomarkers. The kidneys play a central role in metabolic homeostasis, and impaired kidney function leads to metabolite level changes in plasma and urine. Discussion of representative papers performing metabolomics on plasma and urine samples from KT patients. Accurate prediction of rejection status using specific metabolite panels and a potential ability to determine the type of rejection (ABMR vs. TCMR). Survey of the KT metabolomics literature. Despite a general low concordance between studies due to differences in sample cohorts and analytical methodologies, multiple metabolite markers surface across multiple studies. Metabolic alterations observed with rejection across multiple studies include phenylalanine (directly metabolized by the kidney), symmetric dimethylarginine (a uremic toxin known to accumulate in plasma with compromised kidney function) and tryptophan (a precursor for kynurenine in immune-mediated responses). Multi-metabolite panels may provide earlier and more detailed insights into graft injury. Combination with protein and/or RNA biomarkers (smart biomarker panels) may further boost test performance.