Introduction: Expanded hemodialysis (HD using a medium cut-off dialyzer [HD + MCO]) provides comparable or better removal of various uremic toxins, particularly large middle-molecule uremic toxins, than post-dilution online hemodiafiltration (olHDF). Uremic toxin-removing effectiveness between HD + MCO and mixed-dilution olHDF, one of the currently most efficient olHDF modalities, has not been assessed. Method: This randomized controlled trial was conducted in 14 prevalent thrice-a-week HD patients with blood flow rate above 400 mL/min. The patients were randomized into two sequences of 2-week treatment periods of HD + MCO and later mixed-dilution olHDF or vice versa. The reduction ratio (RR) values of small-molecule as well as middle-molecule uremic toxins and protein-bound uremic toxins were measured at baseline and at the end of the treatment. Results: When compared with mixed-dilution olHDF, HD + MCO provided slightly lower β2M RR, but the value was still higher than 75%; showed similar κFLC RR, IS RR, and URR; and yielded significantly higher RR values of α1M (p < 0.001) and λFLC (p < 0.001). Despite higher albumin loss in HD + MCO, the serum albumin levels at the end of the study were comparable between both groups. Conclusion: Expanded HD (HD + MCO) provided similar effectiveness in removing various uremic toxins and could exhibit greater removal of large middle-molecule uremic toxins, such as α1M and λFLC. Expanded HD can be used as an effective alternative option for mixed-dilution olHDF.

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