In the last few years, renewed interest in daily short hemodialysis (DHD; six 2-hour sessions per week) has become apparent as a consequence of the better clinical outcome of patients treated by this schedule. Uremic syndrome is characterized by the retention of a large number of toxins with different molecular masses and chemical properties. Some toxins are water soluble and non-protein bound, whereas others are partially lipophilic and protein bound. There is increased evidence that protein-bound toxins are responsible for the biochemical and functional alterations present in uremic syndrome, and the kinetics of urea is not applicable to these substances for their removal. The aim of this study is to investigate whether DHD is accompanied by increased removal of non-protein-bound and protein-bound toxins and a decrease in their prehemodialysis (pre-HD) serum levels. We studied 14 patients with end-stage renal disease treated by standard HD (SHD; three 4-hour sessions per week) for at least 6 months and randomly assigned them to a two-period crossover study (SHD to DHD and DHD to SHD). Patients maintained the same dialyzer, dialysate, and Kt/V during the entire study. At the end of 6 months of SHD and 6 months of DHD, we evaluated hemoglobin levels, hematocrits, recombinant human erythropoietin doses, and pre-HD and post-HD concentrations of serum urea, creatinine, uric acid, and the following protein-bound toxins: 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, p-cresol, indole-3-acetic acid, indoxyl sulfate, and hippuric acid. Values for hemoglobin, hematocrit, and recombinant human erythropoietin dose did not change during the two study periods. Pre-HD concentrations of creatinine, urea, and uric acid decreased on DHD (creatinine, from 8.7 +/- 1.9 to 7.8 +/- 1.6 mg/dL; P < 0.05; urea, from 149.4 +/- 28.8 to 132.7 +/- 40 mg/dL; P = 0.05; uric acid, from 9.14 +/- 1.49 to 8.16 +/- 1.98 mg/dL; P = 0.06). Concerning protein-bound toxins, lower pre-HD levels during DHD were reported for indole-3-acetic acid (SHD, 0.16 +/- 0.04 mg/dL; DHD, 0.13 +/- 0.03 mg/dL; P = 0.01), indoxyl sulfate (SHD, 3.35 +/- 1.68 mg/dL; DHD, 2.85 +/- 1.08 mg/dL; P = 0.02), and p-cresol at the borderline of significance (SHD, 0.96 +/- 0.59 mg/dL; DHD, 0.78 +/- 0.33 mg/dL; P = 0.07). Such non-protein-bound compounds as uric acid, creatinine, and urea were removed significantly better by DHD, and pre-HD serum levels were reduced. Furthermore, pre-HD concentrations of some protein-bound solutes, such as indole-3-acetic acid, indoxyl sulfate, and p-cresol, also were lower during DHD. Copyright 2002 by the National Kidney Foundation, Inc.