Background. Compared to high-flux dialysis membranes, novel medium cut-off (MCO) membranes show greater permeability for larger middle molecules. Methods. In two prospective, open-label, controlled, randomized, crossover pilot studies, 39 prevalent hemodialysis (HD) patients were studied in four dialysis treatments as follows: study 1, three MCO prototype dialyzers (AA, BB and CC with increasing permeability) and one high-flux dialyzer in HD; and study 2, two MCO prototype dialyzers (AA and BB) in HD and high-flux dialyzers in HD and hemodiafiltration (HDF). Primary outcome was lambda free light chain (λFLC) overall clearance. Secondary outcomes included overall clearances and pre-to-post-reduction ratios of middle and small molecules, and safety of MCO HD treatments. Results. MCO HD provided greater λFLC overall clearance [least square mean (standard error)] as follows: study 1: MCO AA 8.5 (0.54), MCO BB 11.3 (0.51), MCO CC 15.0 (0.53) versus high-flux HD 3.6 (0.51) mL/min; study 2: MCO AA 10.0 (0.58), MCO BB 12.5 (0.57) versus high-flux HD 4.4 (0.57) and HDF 6.2 (0.58) mL/min. Differences between MCO and high-flux dialyzers were consistently significant in mixed model analysis (each P < 0.001). Reduction ratios of λFLC were greater for MCO. Clearances of α1-microglobulin, complement factor D, kappa FLC (κFLC) and myoglobin were generally greater with MCO than with high-flux HD and similar to or greater than clearances with HDF. Albumin loss was moderate with MCO, but greater than with high-flux HD and HDF. Conclusions. MCO HD removes a wide range of middle molecules more effectively than high-flux HD and even exceeds the performance of high-volume HDF for large solutes, particularly λFLC.

The removal of larger middle molecules, such as free immunoglobulin light chains (FLC), is poor with most currently used dialysis technologies. While hemodiafiltration (HDF) provides enhanced clearance of middle molecules compared to high-flux hemodialysis (HD), this technique is currently not approved in some regions and, hence, not accessible for all patients. The retention of middle molecules is thought to be one factor, which contributes to excessive morbidity and mortality in HD patients. The development of medium cut-off (MCO) dialysis membranes is aimed at a more efficient clearance of larger uremic toxins while retaining albumin and may extend the benefit of enhanced solute removal to more patients. In 2 pilot studies, the removal of middle molecules using HD with an MCO dialyzer prototype was compared to (1) high-flux HD and (2) high-flux HD and HDF. The primary outcome was the overall clearance of λ FLC, and the secondary outcome was the clearance of other middle molecules and safety. Pre-to-post reduction ratios and instantaneous clearances during HD were also assessed. In both trials, the overall λ FLC clearance with MCO HD was significantly larger than with high-flux HD and HDF. Accordingly, instantaneous clearances at 30 and 120 min showed significantly higher removal of λ FLC compared to high-flux HD and HDF. MCO HD provides a more efficient removal of larger middle molecules compared to high-flux HD and HDF. A potential drawback is slightly increased albumin loss, yet preliminary data suggest that this does not lead to perma- nently decreased albumin levels. Thus, MCO HD may present a promising approach to further improve middle molecule removal in maintenance dialysis patients and to extend its benefit to more patients. Effects of Hemodialysis Therapy

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Introduction and Aims: Improving middle molecule removal by hemodialysis (HD) similar to hemodiafiltration (HDF) represents a challenging target for dialysis membrane engineering. In this respect, the loss of essential albumin is regarded as a limiting factor. The present pilot trial compared the clinical performance of two medium cutoff (MCO) dialyzer prototypes differing in albumin permeability with two latest generation high-flux dialyzers used in HD and HDF.Methods: In a prospective, randomized, controlled, crossover trial (NCT02377622) enrolling 20 maintenance dialysis patients, HD with two MCO dialyzers (MCO-HD 400 AA and BB, resp.; polyarylethersulfone, 1.7 m², Gambro Dialysatoren GmbH, Germany) was compared to HD with a high-flux dialyzer (Fresenius FX CorDiax 80; polysulfone, 1.8 m²) and high convective volume postdilution HDF (Fresenius FX CorDiax 800; polysulfone, 2.0 m²). Blood flow rate (400 ± 0 mL/min) and individual treatment times (4-5 h) were always identical. Dialysate flow rate was set at 600 mL/ min in HD and at 700 -Q inf mL/min in HDF. The target convective volume in HDF was ≥ 23 L. Primary outcome was the overall clearance (K ovr ) of lambda Ig free light chains (λFLC; 45 kDa). Secondary outcomes included the reduction ratio (RR) for λFLC and removal (K ovr and RR) of other middle molecules in a range between β2-microglobulin (b2M; 11.6 kDa) and λFLC as well as albumin (67 kDa) loss into dialysate. Least square means and standard errors were calculated. Analyses were conducted with a mixed model appropriate for a cross-over design. Results: For λFLC, K ovr and RR of MCO-AA (10.0 (0.58) mL/min; 48.1 (1.72) %) and MCO-BB (12.5 (0.57) mL/min; 52.7 (1.72) %) were largely superior (each P < 0.001) compared to high-flux HD (4.4 (0.57) mL/min; 27.6 (1.72) %) and HDF (6.2 (0.58) mL/min; 37.9 (1.76) %). This finding was also confirmed for most middle molecules larger than b2M. Albumin losses of MCO-AA (3.0 (0.20) g) and MCO-BB (4.6 (0.19) g) were higher (each P < 0.001) compared to the controls in HD (0.2 (0.19) g) and HDF (0.5 (0.19) g). Conclusions: Compared to high-flux HD and HDF, medium cutoff HD removed λFLC and other middle molecules more efficiently at moderate albumin loss. Therefore, medium cutoff HD may have beneficial effects on outcomes of maintenance dialysis patients similar to high convective volume HDF.