Hemodialysis removes protective metabolites and disrupts mitochondrial function

Abstract Background Metabolic analyses offer valuable insights into the biochemical changes induced by hemodialysis, yet prior studies have focused on targeted approaches or lacked comprehensive pathway analysis. This study employs semi-targeted metabolomics to explore metabolic shifts in hemodialysis patients. Methods Pre- and post- dialysis plasma samples were collected from 43 hemodialysis patients and analyzed using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QToF-MS). Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to assess metabolic separation, and variable importance in projection (VIP) scores ranked the most significant metabolites. Results Hemodialysis significantly altered the plasma metabolome, with 79 metabolites showing relevant changes. Most were reduced, including harmful solutes like 3-indoxyl sulfate (FC: 0.29-fold) and D-galactonic acid (0.14-fold), but also protective compounds such as L-carnitine (0.38-fold), quinic acid (0.16-fold) and homocarnosine (0.15-fold). Meanwhile, lipotoxic intermediates like myristic acid (2.51-fold) and linoleic acid (2.28-fold) increased. Enrichment analysis revealed disruptions in amino acid, lipid, and energy metabolism, underscoring the dual impact of dialysis on both toxic and beneficial metabolites. Conclusions Hemodialysis alters the plasma metabolome by removing toxins but also depleting protective metabolites and promoting lipotoxic intermediates. These shifts may undermine therapy benefits, highlighting the need for strategies that preserve metabolic homeostasis in dialysis patients.