Abstract Background and Aims Supra HFR is an extracorporeal purification system in which convection, diffusion, and adsorption act separately. Thanks to a first hemofilter with a sieving coefficient for albumin of 0.02, the endogenous ultrafiltrate is purified by a neutral styrenic resin, then the reconstituted whole blood is led to a second low-flux filter. Recently, an evolution of Supra HFR, called Supra H, has been produced with the innovative second high-flux filter (Bellco, Mirandola, Italy, Kuf > 50 ml/h/mmHg). Aim of the study is a comparison between Supra HFR, Supra H and Supra H used in a reversed configuration, called “reversed Supra H”. The potential advantage of reversed Supra H is to achieve a fine tuning on the removal of medium molecular weight toxins through adsorption acting after the bulky tuning of these molecules with the new high-flux filter (Fig. 1). Method A pilot study was conducted on 4 patients in a cross-over manner. Each patient underwent one session of conventional Supra HFR, one session of Supra H, and one session of reversed Supra H. The median age of the patients was 61 (58-79) years, dialysis vintage was 113 (76-434) months, median blood flow from the vascular access was 300 (270-300) ml/min, dialysis time was 240 (225-240) minutes, and the amount of the endogenous ultrafiltrate (Qinf) produced was kept constant for each patient during the 3 different treatments and was 9.6 (9.2-12) liters. The medium molecular weight toxins studied were β2 microglobulin (β2M), myoglobin and free light chains κ and λ (FLC κ and λ). Albumin removal by all three methods was also studied. The removal of the studied substances was obtained by Reduction Rate per session (RRs) = [(dialysis start value-dialysis end value) / dialysis start value] *100. The dialysis end value was obtained by the stop dialysate flow method and corrected for hemoconcentration according to Schneditz D et al. ASAIO J 2012. Friedman's test was used to analyze the difference between the three groups. Dunn's post-hoc test was conducted to find differences between two groups at a time. Results Regarding the toxic substances studied, the dialysis start values were represented in Table 1. As to the β2M RRs the comparison of Supra HFR vs Supra H vs reversed Supra H was statistically significant in favor of using reversed Supra H (P=0.037), the same result was obtained for the RRs of FLCs κ (P=0.041). Dunn's test showed a significant increase in RRs of FLC κ with reversed Supra H compared with Supra HFR (P=0.040). No significant differences were found for the RRs of myoglobin and FLCs λ although reversed Supra H showed a better trend in the purification of these molecules (Fig. 2). RRs of albumin were similar with these three dialysis techniques. Conclusion The Supra H technique allows an increase in the RRs of tested uremic toxins compared to the RRs obtained by Supra HFR in the conventional version. The reversed Supra H configuration confirms the hypothesis of an even better depurative trend than the other two techniques. The significance of the results is certainly affected by the small number of patients enrolled.