Plasma Metabolites Associated with CKD Stage in Autosomal Dominant Tubulointerstitial Kidney Disease

Background: Metabolomic profiling has not yet been performed in autosomal dominant tubulointerstitial kidney disease (ADTKD) due to UMOD or MUC1 mutations and could provide valuable insights into the pathophysiology of these conditions and identify biomarkers of disease activity. Methods: Untargeted metabolomic analysis of plasma samples was performed on a cohort comprising 40 controls, 51 individuals with ADTKD- UMOD and 49 individuals with ADTKD- MUC1 with CKD stages ranging from 1 to 4. Results: Principal component analysis and hierarchical clustering revealed that the metabolic profiles of controls and ADTKD- UMOD and ADTKD- MUC1 patients with CKD stages 1 and 2 were similar. The metabolome was also similar between ADTKD- UMOD and ADTKD- MUC1 patients at each stage of CKD. Compared to stage 2 CKD, stage 3 CKD was characterized by an increased kynurenine-to-tryptophan ratio indicating activation of indoleamine 2,3-dioxygenase (IDO1), an inflammation-induced and rate-limiting enzyme of tryptophan metabolism, and increased levels of pseudouridine, 3-indoxylsulfate, N-formylmethione, N-acetylated amino acids, acylcarnitines, and several other metabolites. In total, 121 metabolites were identified as significantly altered in stage 4 patients compared to controls. Enrichment analysis of this set revealed that the most significant alterations were in the biosynthesis of arginine and branched-chain amino acids, carnitine synthesis, tRNA metabolism, tryptophan catabolism, urea cycle, metabolism of amino acids, glucose homeostasis and SLC-mediated transmembrane transport. Conclusions: Patients with ADTKD- UMOD and ADTKD- MUC1 had similar metabolomic profiles across CKD stages. While ADTKD is a tubulointerstitial kidney disease rather than glomerular, the effects on the metabolomic pathways appear comparable to other forms of CKD. The kynurenine-to-tryptophan ratio appears to be a promising biomarker of ADTKD progression and will require further study.