The cause of the uremic syndrome [in humans] remains unknown; the success of dialysis therapy suggests that retained, dialyzable but unidentified toxic solutes may play a role. Since chronic peritoneal dialysis seems to prevent or improve uremic neuropathy as well as does hemodialysis, retained solutes of middle MW (500-5000 daltons) may be major toxins. Only body fluid concentrations of these larger solutes were reduced by peritoneal dialysis as well as hemodialysis, whereas small solute concentrations were relatively poorly controlled. Numerous hemodialysis studies examined the toxic potential of middle molecules, as compared with that of smaller solutes. Although the importance of middle molecules as toxins remains unproved, numerous factors influencing their concentrations in body fluid are known. A surprising tolerance of patients to many variations in dialysis strategies was found.