Extracorporeal strategies for the removal of middle molecules

Uremic toxins with a molecular weight of less than 500 Da are classified as small nitrogenous waste products. They are highly water soluble, relatively homogeneous, and have no protein binding. Other uremic retention toxins differ significantly from the small nitrogenous metabolite class in molecular weight, heterogeneity, protein binding, and hydrophobicity. The European Uremic Toxin Work Group subdivided molecules into two categories: protein-bound solutes and middle molecules. Middle molecules were defined as toxins in the molecular weight range of 500-60,000 Da, which exceeds the molecular weight of 2000 Da defined in the original middle molecule hypothesis. Under this new proposed definition, most of these middle molecules are low molecular weight peptides and proteins (LMWPs). This concise review focuses on LMWPs. The metabolism of LMWPs is described, including molecular weight, physical conformation, and charge. Factors influencing dialytic removal of LMWPs such as membrane characteristics, protein-membrane interactions, and solute removal mechanisms, as well as strategies to enhance clearance of these compounds are discussed.