Increasing the Removal of Large Solutes by Kidney Replacement Therapy

Abstract Solutes that accumulate when the kidneys fail range in size from about 40 to 40,000 Da. Their dialytic clearance tends to decrease as their size increases. Disproportionate accumulation of large solutes has therefore long been considered a potential contributor to residual illness in dialysis patients. Early efforts focused on the removal of "middle molecules" with mass from 300 to 2000 Da. The identification of amyloidosis caused by ß 2 microglobulin (ß 2 M) with mass 12,000 Da shifted the focus to low molecular weight proteins. High-flux dialysis and hemodiafiltration increase the clearance of these larger solutes. However non-kidney clearance and solute compartmentalization limit the extent to which their plasma levels can be lowered by increasing their clearance during treatments of standard duration. Clinical benefits of high-volume hemodiafiltration thus cannot readily be accounted for by a reduction in the levels of known large solutes. The accumulation of peptides in the original middle molecular range and the clearance of larger solutes by peritoneal dialysis has been largely neglected. There is new interest in increasing the clearance of solutes even larger than ß 2 M by "extended dialysis." Ongoing clinical trials will extend our knowledge of the effects of extended dialysis and hemodiafiltration. In the future we might more effectively reduce plasma large solute levels by manipulating their non-kidney clearance, which is now poorly understood. ß 2 M is the only large solute whose accumulation in kidney failure has been shown to have specific ill effects. Identification of the ill effects of other large solutes might prompt the development of more targeted therapies.