End-stage renal disease (ESRD) patients rely on renal replacement therapies to survive. Hemodialysis (HD), the most widely applied treatment, is responsible for the removal of excess fluid and uremic toxins (UTs) from blood, particularly those with low molecular weight (MW < 500 Da). The development of high-flux membranes and more efficient treatment modes, such as hemodiafiltration, have resulted in improved removal rates of UTs in the middle molecular weight range. However, the concentrations of protein-bound uremic toxins (PBUTs) remain essentially untouched. Due to the high binding affinity to large proteins, such as albumin, PBUTs form large complexes (MW > 66 kDa) which are not removed during HD and their accumulation has been strongly associated with the increased morbidity and mortality of patients with ESRD. In this review, we describe adsorption- and displacement-based approaches currently being studied to enhance the removal of PBUTs. The development of mixed matrix membranes (MMMs) with selective adsorption properties, infusion of compounds capable of displacing UTs from their binding site on albumin, and competitive binding membranes show promising results, but the road to clinical application is still long, and further investigation is required.

A novel cellulose acetate-based monophasic hybrid skinned amine-functionalized CA-SiO₂-(CH₂)₃NH₂ membrane was synthesized using an innovative method which combines the phase inversion and sol-gel techniques. Morphological characterization was performed by scanning electron microscopy (SEM), and the chemical composition was analyzed by Fourier transform infrared spectroscopy in attenuated total reflection mode (ATR-FTIR). The characterization of the monophasic hybrid CA-SiO₂-(CH₂)₃NH₂ membrane in terms of permeation properties was carried out in an in-house-built single hemodialysis membrane module (SHDMM) under dynamic conditions. Permeation experiments were performed to determine the hydraulic permeability (Lp), molecular weight cut-off (MWCO) and the rejection coefficients to urea, creatinine, uric acid, and albumin. SEM confirmed the existence of a very thin (<1 µm) top dense layer and a much thicker bottom porous surface, and ATR-FTIR showed the main bands belonging to the CA-based membranes. Permeation studies revealed that the Lp and MWCO of the CA-SiO₂-(CH₂)₃NH₂ membrane were 66.61 kg·h⁻¹·m⁻²·bar⁻¹ and 24.5 kDa, respectively, and that the Lp was 1.8 times higher compared to a pure CA membrane. Furthermore, the CA-SiO₂-(CH₂)₃NH₂ membrane fully permeated urea, creatinine, and uric acid while completely retaining albumin. Long-term filtration studies of albumin solutions indicated that fouling does not occur at the surface of the CA-SiO₂-(CH₂)₃NH₂ membrane.