Comparative metabolomic study of high-flux hemodialysis and high volume online hemodiafiltration in the removal of uremic toxins using 1H NMR spectroscopy.

Uremic toxins (UTs) accumulate in the circulation of patients with chronic kidney disease (CKD). High volume hemodiafiltration (HDF) improves clearance of low and medium molecular weight UTs compared to HD. The present study is a post-hoc analysis comparing the metabolomic profile in serum from patients under high flux HD (hf-HD) and HDF in HDFIT, a multicentric randomized controlled trial (RCTs). Per protocol, serum samples were collected pre- and post- dialysis treatments at randomization (baseline) and at the end of the follow up (6 months) and stored in a biorepository. Random (pre- and post-dialysis) samples from nine patients in study arm were selected at baseline and at the end of the follow up. To compare the samples, 26 possibly matching metabolites were identified by a t-test among the four groups using 1H nuclear magnetic resonance (NMR). To evaluate the comparison between the modalities is a single treatment session, the clearance rates (CRs) of each metabolite were calculated based on pre-dialysis and post-dialysis samples. In addition, to evaluate to effect of UT removal during the trial follow up period, the pre-dialysis metabolite concentrations at the baseline and at 6 months were compared among the two arms of the study. There was no significant difference between in the single session CRs of metabolites when hf-HD and HDF were compared. On the other hand, the comparison between baseline and 6-month (long-term evolution) led to the identification of 16 metabolites that differentiated the hf-HD and the HDF evolutions. Most of these 16 metabolites are involved in several important metabolic pathways, such as metabolism of phenylalanine and biosynthesis of phenylalanine, tyrosine, and tryptophan, which are related to UTs and cardiovascular disease development. Although no difference was observed between hf-HD and HDF samples before and after a single session, concentrations of CKD-relevant metabolites and associated pathologies were stable in the HDF samples, but not in the hf-HD samples, over the six-month period, suggesting that HDF enhances long-term stability.

How do Uremic Toxins Affect the Endothelium?

Uremic toxins can induce endothelial dysfunction in patients with chronic kidney disease (CKD). Indeed, the structure of the endothelial monolayer is damaged in CKD, and studies have shown that the uremic toxins contribute to the loss of cell-cell junctions, increasing permeability. Membrane proteins, such as transporters and receptors, can mediate the interaction between uremic toxins and endothelial cells. In these cells, uremic toxins induce oxidative stress and activation of signaling pathways, including the aryl hydrocarbon receptor (AhR), nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) pathways. The activation of these pathways leads to overexpression of proinflammatory (e.g., monocyte chemoattractant protein-1, E-selectin) and prothrombotic (e.g., tissue factor) proteins. Uremic toxins also induce the formation of endothelial microparticles (EMPs), which can lead to the activation and dysfunction of other cells, and modulate the expression of microRNAs that have an important role in the regulation of cellular processes. The resulting endothelial dysfunction contributes to the pathogenesis of cardiovascular diseases, such as atherosclerosis and thrombotic events. Therefore, uremic toxins as well as the pathways they modulated may be potential targets for therapies in order to improve treatment for patients with CKD.