Multi-omics reveals selective metabolic remodeling with trace element supplementation in chronic kidney disease
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Introduction
Chronic kidney disease (CKD) generates metabolically heterogeneous stress across circulating, microbial, and renal compartments. Trace element supplementation may engage redox and metabolic pathways and selectively modulate responsive metabolic programs.
Objectives
To define the metabolic branch selectivity, renal regional distribution, and tissue correlates of responses to a trace element cocktail (TEX) through an integrated clinical-to-mouse multi-omics framework, and to organize these findings into an experimentally testable model.
Methods
In a double-blind, placebo-controlled trial, 80 adults receiving maintenance hemodialysis received standard care plus TEX (20 mL/day; n = 40) or standard care plus matched placebo (n = 40). Longitudinal clinical outcomes were analyzed using participant random-intercept models. Endpoint plasma metabolomics and fecal metagenomics included healthy controls (n = 10) and voluntary trial subsets (placebo, n = 12; TEX, n = 20). Mice with 5/6 nephrectomy underwent targeted tryptophan metabolite profiling, renal spatial metabolomics, histopathology, and molecular analyses.
Results
Longitudinal monitoring showed no overt treatment-related laboratory safety signal. Plasma metabolomics identified treatment-associated differences (false discovery rate <0.05), including directional shifts in phospholipid and amino acid modules toward healthy reference profiles. Integrated microbial and targeted metabolic analyses resolved branch-selective responses, with TEX reducing 3-hydroxykynurenine, kynurenic acid, and xanthurenic acid and shifting the host kynurenine-branch score toward the sham profile in CKD mice. Spatial metabolomics mapped region-specific renal responses, and tissue analyses identified reduced collagen I accumulation together with increased AQP1, SIRT3, SOD2, and NRF2 signals.
Conclusion
This study establishes branch selectivity and renal regional specificity as defining features of TEX-associated metabolic remodeling in CKD. The integrated evidence defines a spatially organized, kynurenine-centered metabolic–renal response architecture comprising host kynurenine-branch remodeling, anatomically patterned renal metabolic responses, and selective structural, tubular, and mitochondrial/redox phenotypes, with kynurenine–mitochondrial/redox coupling as the central mechanistic proposition.
Trial registration
International Traditional Medicine Clinical Trial Registry, ITMCTR2026000263; retrospectively registered on 3 February 2026, after completion of recruitment and follow-up.
