New insights in uremic toxins RAYMOND VANHOLDER, GRIET GLORIEUX, RITA DE SMET, NORBERT LAMEIRE, for the EUROPEAN UREMIC TOXIN WORK GROUP (EUTOX)1

New insights in uremic toxins. The retention in the body of The retention compounds, which are considered recompounds, which normally are secreted into the urine results sponsible for the uremic syndrome, are uremic toxins. in a clinical picture, called the uremic syndrome. The retention Before a retention solute can be accepted as a true urecompounds responsible for the uremic syndrome are called mic toxin, it should comply, however, with a number of uremic toxins. Only a few of the uremic retention solutes fully conditions: (1) Such a compound should be chemically conform to a true definition of uremic toxins. Uremic patients develop atheromatotic vascular disease more frequently and identified and accurate quantitative analysis in biological earlier than the general population. The classical risk factors fluids should be possible; (2) the total body and plasma seem to be less important. Other factors have been suggested levels should be higher in uremic than in nonuremic to be at play, and among those uremic toxins are mentioned subjects. (3) high concentrations should be related to as potential culprits. The identification, classification and charspecific uremic dysfunctions and/or symptoms that deacterization of the solutes responsible for vascular problems seems of utmost importance but is far from complete due crease or disappear when the concentration is reduced; to a lack of standardization and organization. The European (4) biological activity, conforming to clinical changes obUremic Toxin Work Group (EUTox) has as a primary aim to served in conjunction with the uremic syndrome, should discuss, analyze and offer guidelines in matters related to the be proven in in vivo, ex vivo, or in vitro studies; and (5) identification, characterization, analytical determination and evaluation of biological activity of uremic retention solutes. concentrations in these studies should conform to those The final aim remains the development of new strategies to found in body fluids or tissue of uremic patients [5]. reduce the concentration of the most active uremic solutes. Obviously, only a few of the uremic retention solutes These activities will at first be concentrated on reducing factors fully conform to the definition of a true uremic toxin, influencing cardiovascular morbidity and mortality. and even those might be a matter of debate (e.g., H2O, phosphate, potassium, 2-microglobulin). One of the maDEFINITIONS jor problems arising in this area is that many of the Since many decades, the problem of uremic toxicity compounds with a presumed or proven biologic potential has been a major area of concern for the entire nephroare difficult to remove by conventional dialysis, either belogic community. The retention in the body of comcause of their molecular weight and/or as a consequence pounds that normally are secreted into the urine by the of their protein binding. As a result, number 3 of the healthy kidneys gives rise to a progressive deterioration above-mentioned conditions is especially difficult to corof physiologic functions and of the clinical condition. roborate. On the other hand, if clinical proof of benefit The resulting clinical picture is the uremic syndrome. by removal remains absent, the impetus for researchers If uremic retention solutes are considered as such withor industries to produce devices or other methodologies out necessarily proven toxicity, at least 90 organic comof potential help for the removal of these molecules pounds have been retained in uremia [1]. The most imusually remains minimal. This results in a vicious circle, portant known organic uremic retention solutes are whereby technologic/pharmacologic innovations to relisted in Table 1. To this list should be added a number move solutes other than the classic compounds, such as of inorganic substances, such as water, potassium, phosurea, are limited or even nonexistent. phate, and the trace elements [2–4]. This is probably only the tip of the iceberg, and many more still unidentified UREA AS A UREMIC RETENTION SOLUTE/ solutes are possibly retained and might exert toxicity. UREMIC TOXIN