New uremic toxins - which solutes should be removed?

Chronic kidney disease (CKD) is characterized by the progressive retention of a myriad of compounds, several of which play a role in cardiovascular damage, a major cause of mortality in CKD. Over the past years, especially protein-bound compounds (e.g. indoxylsulfate and p-cresylsulfate) and/or middle molecules (e.g. AGEs, cytokines and dinucleoside polyphosphates) have been identified as some of the main toxins involved in vascular lesions affecting endothelial cell, leukocyte, platelet and/or vascular smooth muscle cell function in CKD. Many of these solutes, however, are difficult to remove by standard dialysis strategies. The removal of protein-bound solutes remains limited because only the free fraction of the solute is available for, mostly diffusive, removal, while removal of the larger middle molecules (mostly larger peptidic compounds) can be obtained by increasing dialyzer pore size and by applying convective strategies. In addition, new therapeutic strategies pursuing specific removal (e.g. by adsorption) and/ or pharmacological neutralization of the molecular impact of the responsible compounds are explored, aiming at an improved outcome in CKD patients.