During the progression of renal failure, a host of compound is retained in the body of uremic patients; those compounds are excreted by the healthy kidneys under normal conditions. About 100 retention solutes have been recognized at present [1]. Not all of these compounds are necessarily toxic. They can only be defined as uremic toxins if they have been proven to exert biochemical/biological action. [1] Vanholder RC. Retention pattern of uremic solutes: An analysis of the current knowledge (abstract). J Am Soc Nephrol. 2001; 10(12):87A.

1. The small water soluble compounds (MW: <500 Da), such as urea (MW: 60 Da). These are relatively easy to remove by standard dialysis membranes (small pore size – low flux).

2. The small protein-bound solutes (MW also mostly <500Da), such as p-cresol (MW: 108 Da). Dialytic removal of these solutes is hampered by their protein binding, irrespective of the membrane type. This results in a behavior comparable to that of the larger molecules. It is of note that also some larger molecules, such as leptin, are protein bound.

3. The so-called middle molecules (MW: >500Da such as b2-microglobulin (MW: 11,818 Da). Originally, the upper molecular weight range proposed for the middle molecules was  12,000 Da. In the meantime, larger molecules with a biological impact have been recognized, e.g., leptin (16,000 Da). Hemodial Int. 2003; 7(2):156–161. Inadequate removal of a large number of potentiall toxic organic metabolites from the vascular bed into the urine in the course of acute kidney injury (AKI) and chronic kidney disease (CKD) is associated with various clinical symptoms which are often difficult to interpret. Uremic retention solutes are referred to as uremic toxins when they interact with normal biological functions. It is of considerable importance to identify which of the uremic retention solutes are actually uremic toxins and what pathomechanisms are involved in their damaging effect on the kidneys and other organs. The term uremic syndrome refers to the clinical picture produced by accumulation in the body of noxious substances which in health are eliminated into the urine. Although the clinical symptoms of uremic syndrome have been known for decades, our knowledge of the origin, chemical structure and composition of the retained endogenous substances responsible for these symptoms is far from complete CLASSIFICATION Based in water solubility, protein binding capacity, molecular weight, pattern of removal by dialysis, biological properties and potential to produce clinical symptoms. The most common classification of uremic compounds into 3 groups proposed by EUTox is by molecular weight, protein-binding capacity and removal pattern by dialysis:

4. Low-Molecular-Weight Water-Soluble Uremic Toxins This group consists of small molecules (molecular weight <500 Da) that are soluble in water and easily removed by any dialysis strategy. Low-molecular-weight organic compounds may occur in free water-soluble form or bound to plasma proteins, which alters the function of both the toxin and the transporter protein. Of the 90 molecules evaluated by EUTox, 68 were found to be members of this group, the most common compounds being ADMA (asymmetric dimethylarginine), creatine, creatinine, hyaluronic acid, guanidine, guanidinoacetate, guanidinosuccinate, oxalate, SDMA (symmetric dimethylarginine), urea and uric acid.

5. Protein-Bound Solutes Twenty-five uremic retention solutes, i.e. 27.8% of all uremic compounds evaluated by EUTox, are included in the protein-bound solutes group. Although the molecular weight of most members of this group is less than 500 Da, because of their protein-binding capacity they are recognized as ‘difficult to remove’ by dialysis. The main protein-bound solutes include advanced glycation end products (AGEs), carboxy methyl propyl furanpropionic acid, cytokines, interleukins, tumor necrosis factor-α (TNF-α), dimethylguanidines, hippuric acid, homocysteine, indole-3-acetic acid, indoxyl glucuronide, indoxyl sulfate (IS), kynurenic acid, kynurenine, leptin, phenolic compounds, p -cresyl sulfate ( p -CS), p -cresyl glucuronide, phenol sulfate, phenol glucuronide, phenylacetic acid, quinolinic acid and retinol-binding protein.

6. Middle-Molecular-Weight Molecules The molecular mass of middle-molecular-weight molecule is above 500 Da. So far more than 50 such compounds have been found to have a cause-and-effect relationship with the origin and development of many pathophysiological processes. Members of this group include adiponectin, cystatin C, leptin, motilin, α1-acid glycoprotein, α1-microglobulin, endothelin, ghrelin, osteocalcin atrial natriuretic peptide, prolactin, retinol-binding protein, β2-microglobulin, cholecystokinin and vasoactive intestinal peptide. The EUTox classification does not describe the toxicity of the compounds listed and so far there has been no effective method of such characterization. It has been suggested that further more precise classification of the compounds should take into consideration any similarities between their chemical structures, common biological or organ function, and the anatomical site of their origin.

Last modified on 2023-04-15

Author: Noble