Metabolomic Insights into Convective and Diffusive Dialysis Therapies: Crossover Evaluation of Expanded Hemodialysis, Online Hemodiafiltration, and High-Flux Hemodialysis

Background: Metabolomics offers a comprehensive tool to identify disruptions in metabolic pathways related to oxidative stress, inflammation, energy metabolism, and nutritional status. This study aimed to compare the metabolic effects of expanded hemodialysis (HDx) and online hemodiafiltration (OL-HDF) with conventional high-flux hemodialysis (HF), using a metabolomics-based analytical approach. Methods: In this single-center, randomized cross-over study, patients were assigned to an initial modality (HDx, OL-HDF, or HF) for a 4 weeks treatment period. Each intervention phase was separated by a 1 week washout period. Plasma samples were collected at the start and end of each treatment phase for metabolomic profiling. Results: Twenty-two patients were included in the study. Multivariate analysis using partial least squares discriminant analysis (PLS_DA) and variable importance of projection (VIP) scores identified several key metabolites contributing to group discrimination. Among the most relevant were hippuric acid, cysteine, 2-oxoglutaric acid, threomic acid, and glutamic acid. A consistent decline in the intensity of threonic acid (VIP) was observed after four weeks across all dialysis modalities (Fig. 1). In contrast, glutamic acid levels increased after treatment, particularly in the HDx group. Conclusion: All identified metabolites demonstrated a gradient pattern, with higher concentrations at baseline and a progressive decline following for weeks of regular dialysis, supporting their classification as uremic toxins or metabolites normally excreted by the kidneys. Notably, glutamic acid exhibited increased expression post-treatment, especially with modalities featuring a stronger convective component. This finding may reflect enhanced nucleotide metabolism, potentially linked to intracellular messengers such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which are critical for cellular signaling and energy metabolism through the Krebs cycle.