AbstractProtein-bound uremic retention solutes accumulate in patients suffering from chronic kidney disease, and the removal of these solutes by hemodialysis is hampered. Therefore, we developed a dialysis technique where the protein-bound uremic retention solutes are removed more efficiently under high ionic strength. Protein-bound uremic solutes such as phenylacetic acid, indoxyl sulfate, and p-cresyl sulfate were combined with plasma in the presence of increased ionic strength. The protein integrity of proteins and enzymatic activities were analyzed. In vitro dialysis of albumin solution was performed to investigate the clearance of the bound uremic retention solutes. In vitro hemodiafiltrations of human blood were performed to investigate the influence of increased ionic strength on blood cell survival. The protein-bound fraction of phenylacetic acid, indoxyl sulfate, and p-cresyl sulfate was significantly decreased from 59.4% ± 3.4%, 95.7% ± 0.6%, 96.9% ± 1.5% to 36.4% ± 3.7%, 87.8% ± 0.6%, and 90.8% ± 1.3%, respectively. The percentage of phenylacetic acid, indoxyl sulfate, and p-cresyl sulfate released from protein was 23.0% ± 5.7%, 7.9% ± 1.1%, and 6.1% ± 0.2%, respectively. The clearance during in vitro dialysis was increased by 13.1% ± 3.6%, 68.8% ± 15.1%, and 53.6% ± 10.2%, respectively. There was no difference in NaCl concentrations at the outlet of the dialyzer using isotonic and hypertonic solutions. In conclusion, this study forms the basis for establishing a novel therapeutic approach to remove protein-bound retention solutes.