Background: Online hemodiafiltration (HDF) represents the most advanced form of kidney replacement therapy, combining diffusive and convective transport to enhance the removal of uremic toxins across a wide molecular spectrum. Achieving high convective volumes is a key determinant of treatment efficacy and has been associated with improved survival. Beyond small solutes, HDF targets middle molecules and protein-bound uremic toxins (PBUTs), including β2-microglobulin, inflammatory cytokines, and other large uremic compounds implicated in cardiovascular and systemic complications. Aims: This narrative review examines advances in dialysis membrane materials, dialyzer design, and monitoring technologies that optimize mass transfer in HDF. It focuses on the interplay between membrane permeability, hemocompatibility, and convective dose delivery, and discusses how these engineering developments translate into clinical performance. Key mechanisms: Recent progress in synthetic polymer membranes, particularly polysulfone- and polyethersulfone-based systems, and hollow-fiber manufacturing has enabled improved control of pore size distribution, hydraulic permeability, and sieving characteristics. These developments enhance the clearance of middle molecules and selected PBUTs while preserving essential proteins such as albumin. Mechanistic insights into internal filtration, protein polarization, and Donnan effects highlight the complex transport processes occurring within the dialyzer and their interaction with automated HDF systems. Expanded hemodialysis and high-volume HDF approaches further increase the removal of larger solutes but require careful management to limit albumin loss and maintain hemocompatibility. Clinical implications: Optimized membrane design, combined with advanced HDF machine algorithms, allows delivery of high convective volumes under safe and stable conditions, improving removal of β2-microglobulin, cytokines, and other clinically relevant toxins associated with inflammation and cardiovascular risk. However, treatment must remain individualized, considering electrolyte balance, albumin preservation, and patient-specific factors such as inflammation and nutritional status. Mechanistic modeling supports understanding of transport phenomena but must be interpreted cautiously when translated into clinical practice. Conclusions: Advances in membrane science, dialyzer engineering, and monitoring technologies have strengthened the role of HDF as a precision-based renal replacement therapy. Continued innovation aimed at optimizing middle-molecule and PBUT clearance while preserving albumin and treatment stability is essential to improve patient outcomes and support the broader implementation of HDF as a mainstream dialysis modality.
Gagel et al. (2026) studied this question.