Classification of Uremic Toxins and Their Role in Kidney Failure

Abstract

Advances in our understanding of uremic retention solutes, and 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 on the basis of 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 the 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 CKD.

Keywords: classification; definition; dialysis; middle molecule; uremia.

Figure 1.

Definition of uremic toxins. The left panel represents the current definition of uremic toxins, with the bold text indicating terminology that we identified as needing an update. The middle panel elaborates on the limitations associated with the identified terms. The right panel shows the newly proposed definition of uremic toxins.

Figure 2.

Uremic toxins and related systemic disorders. The pathophysiologic effect of uremic toxins on organ systems and associated disorders linked with outcomes. Many organ systems influence each other and contribute to kidney damage and cardiovascular morbidity.

Figure 3.

The modeled effect of increasing dialytic clearance on time required to reach solute concentration equilibrium. The modeled effect demonstrates that solutes may be classified according to time to reach steady state. Each panel illustrates the time required for solute concentration to reach equilibrium after an increase in dialytic clearance with 4-hour thrice-weekly treatment. Modeling was performed for four hypothetical solutes with varying dialytic RRs (0% for CMPF [A], 25% for β2-microglobulin [B], 50% for hippurate [C], and 75% for urea [D], respectively). Dialytic clearance was increased two-fold for solutes with RR 25%, 50%, and 75%, and was increased from 0 ml/min to 1 ml/min for the solute with RR 0%. Intercompartmental clearances were assumed to be higher than the dialytic clearance such that the accessible compartment refills rapidly from nonaccessible compartments during dialysis. The RR can therefore refer to blood, plasma, or serum concentrations. Constant generation and absence of nondialytic clearance of each solute were also assumed. Solute concentrations are presented without any unit on the y axis, with the weeks after increase in dialytic clearance on the x axis. The arrow indicates the time at which dialytic clearance is increased. The asterisk (*) indicates the time at which concentrations are within 1% of equilibrium for each solute during each week of dialysis from then on. The dashed blue line represents the average solute concentration over each week. CMPF, 3-Carboxy-4-methyl-5-propyl-2-furanpropionic acid; RR, reduction ratio.

Figure 4.

New definition and classification of uremic toxins. The third column from right to left subdivides molecules according to their protein affinity and is followed by a column that describes their molecular weight. On the top of each box of the molecular weight column, each colored dialyzer represents a dialysis modality and its expected capacity to remove the substances with molecular mass within the range represented in the box underneath. Although all dialyzer types remove small water-soluble compounds and protein-bound compounds, removal of protein-bound compounds is less pronounced. The black broken line indicates that many compounds with protein binding ≥80% are intestinally generated; the blue broken line indicates that some small water-soluble compounds may be intestinally generated. ADMA, asymmetric dimethylarginine; AGEs, advanced glycosylation end products; CML, carboxymethyl lysine; CXCL12, C-X-C motif chemokine 12; CX3CL1, chemokine (C-X3-C motif) ligand 1; DMA, dimethylamine; FGF, fibroblast growth factor; FLC, free light chain; HCO, high cutoff; Hcy, homocysteine; HD, hemodialysis; HDF, hemodiafiltration; HDx, expanded hemodialysis; IGF-1, insulin-like growth factor-1; IL, interleukin; IS, indoxyl sulfate; MCO, medium cutoff; MMA, monomethylamine; PAG, phenylacetylglutamine; pCS, para-cresyl sulfate; SMDA, symmetric dimethylarginine; sTNFR, soluble tumor necrosis factor receptor; TMA, trimethylamine; TMAO, trimethylamine-N-oxide; YKL-40, chitinase-3-like protein 1.