The removal of protein-bound uremic toxins (PBUTs) from the blood of kidney failure patients with conventional dialysis is limited. However, as their harmful effects and association with morbidity and mortality in dialysis patients are increasingly recognized, PBUTs have become important therapeutic targets. In this review, PBUT removal with current state-of-the-art dialysis technologies and future perspectives are discussed. Strategies to enhance PBUT clearance include methods that interfere with PBUT–albumin binding, such as chemical displacers, high ionic strength, pH changes, or electromagnetic fields, thereby increasing the free fraction available for dialysis. While these methods have shown promise in vitro, and some also in vivo, long-term safety data are lacking. PBUT removal can also be increased by adsorption, either directly via hemoperfusion, or indirectly, e.g., via sorbents incorporated in a mixed-matrix membrane or dissolved in the dialysate. In the kidney, PBUTs are secreted in the proximal tubules; hence, a cell-based bioartificial kidney (BAK) that secretes PBUTs is proposed as an add-on to current dialysis. Yet both PBUT adsorption strategies and, in particular, BAKs face considerable challenges in upscaling and mass production at acceptable costs. In conclusion, many novel technologies are under development, all requiring further (pre)clinical testing and upscaling before these strategies can be applied in the clinic.

Current hemodialysis (HD) methods inefficiently remove protein-bound uremic toxins (PBUTs) due to their high binding affinity to plasma proteins, mainly albumin. This study aimed to investigate electromagnetic (EM) fields and temperature as potential extracorporeal, non-systemic methods to increase HD PBUT clearance. PBUT release was measured in infusible (caprylate-stabilized) albumin solutions spiked with indoxyl sulfate (IS) using an in vitro dialysis setup including a real-time, in-line IS-sensor. No measurable influence on PBUT release was observed during EM field-tests (f = 1–600 MHz, E <= 1 kV/m), but temperature tests (35–40 °C range) showed an absolute increase in IS free fraction of 0.7%/°C. Furthermore, static equilibrium dialysis tests, including IS, p-cresyl sulfate (pCS) and hippuric acid (HA), showed a free fraction increase for all three PBUTs upon a temperature increase from 37 °C to 43 °C (IS 1.30-fold, pCS 1.12-fold, HA 1.15-fold). Mathematical modeling showed a 1.14-fold decrease in plasma IS concentration after 5 weeks of HD, and exploratory hemocompatibility tests did not reveal pronounced changes over 15 heating cycles at 43 °C under static conditions. Extracorporeal temperature elevation is a promising technique to enhance PBUT removal during hemodialysis, which may be easily combined with current HD machines, does not break sterility, and avoids elevating free PBUTs inside the body.

Human serum albumin (HSA) is the most abundant plasma protein and plays essential roles in regulating oncotic pressure, transporting endogenous and exogenous compounds, and maintaining redox balance. Because of its biochemical properties, HSA is widely used in clinical medicine, biotechnology, and pharmaceutical development. However, albumin is not a static molecule. It undergoes numerous post-translational modifications (PTMs), including oxidation, glycation, carbonylation, carbamylation, and aggregation, which can significantly alter its structure, ligand-binding properties, antioxidant capacity, and pharmacokinetics. Furthermore, commercial albumin products exhibit substantial heterogeneity arising from differences in source material, manufacturing processes, formulation conditions, and storage practices. This review summarizes the current understanding of PTMs affecting human serum albumin, with particular emphasis on their molecular origins and functional implications. We discuss how physiological, pathological, and manufacturing-induced modifications influence albumin activity and contribute to variability among commercial albumin products. In addition, we examine established and emerging applications of PTM-modified albumin in diagnostics, critical care, extracorporeal detoxification, drug delivery, nanomedicine, and regenerative medicine. Finally, we highlight current challenges related to product heterogeneity, quality control, regulatory assessment, and discuss future opportunities in albumin-based technologies. A deeper understanding of albumin PTMs is essential for improving critical care and developing next-generation albumin-based biomedical products.