Monitoring of Allograft Adaptation After Kidney Transplantation in Pediatric Patients by Targeted Plasma Metabolomics.

End-stage kidney disease is preferably treated by kidney transplantation. The function of the allograft often determines kidney-controlled processes and requires long-term monitoring. Kidneys are organs with a very high metabolic rate, and, thus, a metabolomics approach is suitable to observe systemic metabolic changes that are related to graft adaptation. To understand these ongoing changes in post-transplant pediatric patients, we applied a targeted liquid chromatography/tandem mass spectrometry-based metabolomics approach. Time-dependent changes of 140 metabolites in plasma samples prospectively collected from 23 pediatric kidney graft recipients receiving tacrolimus-based immunosuppression were monitored over the first 4 years after transplantation and compared to levels prior to transplantation. Furthermore, by comparing the pre-transplant metabolite levels to those measured in healthy children, we were able to obtain insights into the pathways associated with kidney failure. Arginine biosynthesis, alanine, aspartate, glutamine, and glutamate metabolism, taurine and tryptophan metabolism were the most affected pathways that separate the pediatric patients with and without kidney failure. Accumulation of uremic toxins such as various tryptophan/kynurenine and tryptophan/indole metabolism pathway intermediates, and betaine and methionine cycle metabolites was evident in patients with restricted kidney function. Furthermore, reduced nicotinamide production, insufficient hydroxylation of phenylalanine to tyrosine, lowered cysteine, arginine, glutamine, taurine, and overall amino acid utilization, as well as diminished levels of protective antioxidants such as glutathione and vitamins B6 and C, were all the result of progressive kidney failure leading to transplantation. Importantly, following kidney transplantation and recovery of kidney function, the levels of most of the previously described metabolites normalized toward the levels observed in healthy participants. The here identified metabolic patterns could be used as markers to monitor the progression of pediatric chronic kidney disease patients towards kidney failure, and assuming their direct association with kidney function, they could serve as markers of successful graft adaptation.