## 3 Discussion
Finally, in a recent in vitro study, the removal of a broad range of uremic toxins, including IS and hyppuric acid (HA), from human plasma by a carbon-based nanoporous sorbent material (CMK-3 type) which has two distinct pore domains, micropores, and mesopores, was investigated [38]. The authors found that the amount of IS and HA/m2 adsorbed by CMK-3 was slightly higher than carbon-based sorbents with predominant mesoporosity and much higher than carbon-based sorbents with predominant microporosity. The studied materials did not show a tendency to lower total plasma protein levels through 4 hours of direct plasma-sorbent contact showing high potential to be used in extracorporeal blood purification treatments [38]. In our opinion, the interesting data emerging from this pilot study are represented by the combined effect of the symbiotic and the DVB-PVP HD on the reduction in IS and PCS plasma levels in HD patients. In this trial, the use of NATUREN G alone apparently did not seem to be sufficient in reducing pre-HD plasma levels of IS and PCS in traditional bicarbonate dialysis, after 7 weeks of treatment, as compared to baseline and placebo group. Indeed, failure to decrease the pre-dialysis plasma levels of IS and PCS after symbiotic treatment may be due to the multi-compartmental distribution of IS and PCS, as suggested by the two-compartment kinetic model for protein-bound solutes [40]. In this model, all the solutes showed a substantially slower decline of concentration in the extraplasmatic compartment, which is the place where they mainly exert toxicity. In this context, the symbiotic may have gradually reduced the production of IS and PCS over the 7 weeks of treatment, progressively depleting the deposits of uremic toxins in the extraplasmatic compartment [40], and leaving their plasma levels unchanged. The decrease in plasma levels of IS and PCS became visible from the eighth week. At the same time, the innovative DVB-PVP dialysis, adsorbing higher percentages of IS and PCS, made possible the further reduction in uremic toxins both at pre- and post-dialysis levels, resulting in a decrease in the pre-dialysis IS and PCS by 24% and 35%, respectively, and of the post-dialysis IS and PCS by 31% and 47%, respectively, compared to the baseline. This synergy was not found in the placebo group, where it was possible to evaluate the isolate better ability of DVB-PVP HD to remove IS compared to BHD. Effectively, a trend of increased RR% of total IS and, to a lesser extent for total PCS, in both groups A and B, after each DVB-PVP HD session was observed (Table S2: Reduction ratio for total and free IS and PCS concentration at the different dialysis session during the trial in the symbiotic-treated group (group A) and placebo-treated group (group B)), which was more evident in the placebo group, suggesting a better capacity of DVB-PVP HD to remove IS and PCS as compared to BHD. Attempts to manipulate PBUTs production by acting on gut microbiota have been made in the last years. The rationale of this approach is justified by the plastic capacity of gut microbiota to respond to environmental stimuli, primarily nutrition and supplementation [26]. In this regard, our group recently demonstrated that dietary schemes, such as Mediterranean diet and a very low protein diet, are able to modify, in a saccharolytic fashion, gut microbiota in CKD patients and to reduce PCS and IS [41]. Analogously, supplementation with substances capable of inducing beneficial bacteria colonization and/or selective growth, namely probiotics, prebiotics, and synbiotics, seems to represent a promising strategy to reduce PBUTs production [26]. Few papers studied the effects of probiotic administration in HD patients with discrepant results. One trial evidenced the differential efficacy in IS reduction by _Bifidobacterium_ supplements, where the formulation (gastro-resistant capsule vs. powder) seems to be a key element in probiotic colonic delivery [27].