Work

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

Year: 2025

Type: article

Abstract: Key Points This is the first large-scale metabolomic study in genetically confirmed autosomal dominant tubulointerstitial kidney disease (ADTKD), providing a new resource for rare kidney diseases. ADTKD- UMOD and ADTKD- MUC1 are metabolically indistinguishable across stages, supporting the development of unified monitoring strategies. The plasma kynurenine-to-tryptophan ratio increases with CKD progression, supporting its use as a noninvasive marker of inflammation in ADTKD. 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 the 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 patients with ADTKD- UMOD and ADTKD- MUC1 at each stage of CKD. Compared with stage 2 CKD, stage 3 CKD was characterized by an increased kynurenine-to-tryptophan ratio, indicating activation of indoleamine 2,3-dioxygenase, 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 patients in stage 4 compared with 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, transfer RNA metabolism, tryptophan catabolism, urea cycle, metabolism of amino acids, glucose homeostasis, and solute carrier-mediated transmembrane transport. Conclusions Patients with ADTKD- UMOD and ADTKD- MUC1 had similar metabolomic profiles across CKD stages. Although ADTKD is a tubulointerstitial kidney disease rather than glomerular, the effects on the metabolomic pathways appear comparable with those of other forms of CKD. The kynurenine-to-tryptophan ratio appears to be a promising biomarker of ADTKD progression and will require additional study.

Source: Kidney360

DOI: 10.34067/kid.0000001029