Icodextrin (ICO) has better biocompatibility and an improved ultrafiltration profile in long-dwell peritoneal dialysis compared to those of glucose. However, the long-term repeated use of a single ICO osmotic agent may cause a change in the peritoneal transport characteristics, leading to a reduction in the ultrafiltration profile. Many studies have shown that such a reduction can be quite significant in some patients. In this study, the factors responsible for this decline are investigated via a series of numerical simulations. The peritoneal transport characteristics and ultrafiltration profile are predicted using a three-pore model. To account for the continuous absorption of ICO from the abdominal cavity during peritoneal dialysis, the three-pore model is modified to accommodate a non-constant concentration of ICO in blood. The simulation results show that the presence of residual ICO in blood results in poorer ultrafiltration behavior. Long-duration and repeated use and exposure to ICO result in a residual concentration of ICO in blood, which changes the mesothelial tissue around the blood capillaries in the peritoneal membrane and causes a reduction in ultrafiltration performance.