Classification of Uremic Toxins and Their Role in Kidney Failure

Abstract

Advances in our understanding of uremic retention solutes, as well as improvements in hemodialysis membranes and other techniques designed to remove uremic retention solutes, offer opportunities to readdress the definition and classification of uremic toxins. A consensus conference was held to develop recommendations for an updated definition and classification scheme based upon a holistic approach that incorporates physicochemical characteristics, and, dialytic removal patterns of uremic retention solutes and their linkage to clinical symptoms and outcomes. The major focus is on removal of uremic retention solutes by hemodialysis. The identification of representative biomarkers for different classes of uremic retention solutes and their correlation to clinical symptoms and outcomes may facilitate personalized and targeted dialysis prescriptions to improve quality of life, morbidity, and mortality. Recommendations for areas of future research were also formulated, aimed at improving understanding of uremic solutes and improving outcomes in patients with chronic kidney disease.

Involvement of Inflammasome Components in Kidney Disease

“…The serum concentration of IL-1β protein is reported as ~1.5 times higher in uraemia compared to normal, and IL-18 concentration as ~1.4 times higher (The European Uremic Toxins (EUTox) Database, available online at , accessed on 12 November 2021). Interleukin 1β has been classified as belonging to uremic toxins with the second-highest evidence score for toxicity [ 345 ]. Per definition is the retention of uremic solutes directly or indirectly attributable to the reduction in renal clearance [ 346 ].…”

Removal of Protein-Bound Uremic Toxins Using Binding Competitors in Hemodialysis: A Narrative Review

“…When an exogenous compound that binds to the albumin PBUT binding site is introduced, it results in a reduced free protein concentration, leading to a shift in dynamic equilibrium to provide more free protein, as per Le Chatelier's law of chemical equilibria [14] [see Equation (2)]. Thereby, in effect, more toxins also become free and thus dialyzable.…”

“…Uremic toxins have broadly been classified into three categories: (1) small-sized toxins (<500 Da), (2) middle and large-sized uremic toxins (>500 Da), and (3) protein-bound uremic toxins (PBUTs) [1]. In an updated definition, these solutes were further classified based on their origins, molecule weight, and albumin-binding properties [2]. In end-stage kidney disease (ESKD) patients, these toxins accumulate, and patients must undergo dialysis to reduce the levels of these toxins.…”

“…For the prototypical PBUTs indoxyl sulfate (IS) and p-cresyl sulfate (pCS), with known toxicities in chronic kidney disease patients [2,7], the albumin-bound fraction is approximately 95% [3]. The poor removal of PBUTs with conventional HD is evidenced by the fact that pre-dialysis levels of IS and pCS have been found to be as much as 116-fold and 41-fold higher, respectively, than in age-matched healthy controls, while pre-dialysis concentrations of non-protein-bound solutes with comparable molecular weight, such as urea and creatinine, were only 5-and 13-fold higher, respectively [8].…”

Development of online hemodiafiltration in Japan

“…In a recent review, MM was defined as a solute that passes through the glomerulus, with a MW of 0.5-58 kDa, which is the limit of glomerular filtration, and following revisions in MM classification were proposed "small-middle 0.5-15 kDa, " "medium-middle > 15-25 kDa" and "largemiddle > 25-58 kDa" (Fig. 1) [9]. In the future, the selection of blood purification therapy will follow this classification.…”