Targeting large middle molecules: Clinical implications of expanded hemodialysis in hemodialysis care

End-stage kidney disease (ESKD) presents a major clinical burden, with maintenance hemodialysis (HD) patients facing high cardiovascular mortality and impaired quality of life (QoL). Despite advances from low-flux to high-flux HD and the introduction of hemodiafiltration (HDF), clearance of large middle molecules (LMMs >25 kDa) remains inadequate. These molecules contribute to inflammation, oxidative stress, atherogenesis, and mineral-bone disorders, all of which worsen patient outcomes. Expanded hemodialysis (HDx), utilizing medium cutoff membranes, represents a novel approach that combines diffusion and enhanced internal convection to improve LMMs removal, without the need for substitution fluid. This review explores the limitations of conventional HD, the pathological roles of LMMs, and the evolution of dialysis strategies aimed at enhancing solute clearance. Evidence from observational studies, randomized trials, and meta-analyses shows that HDx improves the removal of inflammatory LMMs, reduces hospitalization burden, preserves residual kidney function, and enhances patient-reported outcomes such as recovery time and symptom relief. Furthermore, HDx offers a practical and cost-effective alternative to online HDF (OL-HDF), particularly in the resource-limited settings, achieving comparable efficacy with shorter sessions and lower blood flow requirements. By addressing the key shortcomings of traditional HD and approaching the solute clearance profile of the native kidney, HDx offers a promising advancement in the care of ESKD patients.