An Overview of Uremic Toxicity

About 100 uremic retention solutes have been identified at present, but not all of these compounds are necessarily toxic. They can be defined as uremic toxins if they exert biochemical/biological actions. Based on their physicochemical characteristics, there are three major groups of uremic retention solutes: 1) the small water‐soluble compounds (<500 Da), which are easily removed by standard low‐pore‐size dialyzer membranes; 2) the protein‐bound solutes (also mostly <500 Da), whose dialytic removal is hampered by their protein binding, irrespective of the membrane type; and 3) the so‐called middle molecules (>500 Da), which can be removed only by membranes with a large pore size and/or adsorptive capacity. In the present review, we will summarize the currently known information about the toxicity of the uremic retention solutes. Although removal of small water‐soluble urea has been recognized for many years as a current measure of dialysis adequacy, data on its toxicity are very scanty. Almost 50 other water‐soluble compounds are known to be retained in uremia, but only a few exert biological effects. Most of the toxic water‐soluble moieties, such as the guanidines, phosphate, xanthine, and hypoxanthine show an intra‐dialytic compartmental behavior, which is different from urea. A substantial number of uremic solutes are protein bound, and most of them exert biological action. Among them are the phenols, indoles, homocysteine, and carboxy‐methyl‐propyl‐furanpropionic acid. Recent data suggest that protein binding acts as a buffer against the toxic effects of these compounds, and that hypoalbuminemia increases both their free fraction and their toxicity. In addition, many middle molecules, such as ß₂‐microglobulin, leptin, and advanced glycation end products, have been related to biological/clinical effects. Our current knowledge of the biological impact of the middle molecules is very likely incomplete. It is concluded that many of the water‐soluble compounds exert little or no toxicity, and that urea removal pattern per se is not identical to that of many biologically active molecules. Hence, in dialysis, more than urea removal alone should be pursued.