## 3 Discussion
Very recently, the group of [PERSON] demonstrated the efficacy of a _Lactobacillus Rhammosus_ capsule formulation to reduce phenol and PCS in an RCT carried out in HD patients [28]. On the contrary, the probiotic supplementation of the _Streptococcus thermophilus_, _Lactobacillus acidophilus_ e _Bifidobacterium longum_ capsule failed to reduce uremic toxins and inflammatory markers in HD patients [29]. In peritoneal dialysis patients, a _Bifidobacterium_ spp + _Lactobacillus_ formulation seems to decrease inflammatory cytokine levels, but the trial did not analyze reductions in PBUTs levels [42]. Other trials tested the action of prebiotic supplementation in HD patients. [PERSON] and coworkers demonstrated the efficacy of a 4-weeks' supplementation of oligofructose-enriched inulin in reducing both PCS circulating levels and production rates in HD patients, while IS levels remained unchanged [30]. Differently, the group of [PERSON] recently evidenced the effects of resistant starch in reducing IS and IL-6 [31]. The symbiotic association of prebiotics and probiotics has also been tested in HD. The group of [PERSON] reported a reduction in PCS and amelioration in stool transit and consistency after 2 weeks of a _Lactobacillus casei Shirota_, _Bifidobacterium breve Yakult_, and galactooligosaccharides formulation [32]. Other trials carried out with symbiotic formulations in HD patients did not investigate the modulation of PBUTs levels, rather revealing other beneficial effects on gut microbial composition [43] and amelioration of biomarkers of glucose homeostasis, inflammation, and oxidative stress [44]. The lack of an observed effect in our population by the symbiotic administration after seven weeks could be attributed to several reasons. First of all, the small sample size prevented us from observing even small changes in PBUTs level. Second, a different, gastro-resistant capsule formulation instead of the powder one could have guaranteed better gut colonization. Third, the HD population is characterized by an advanced uremic status in comparison to CKD patients at intermediate stages. Evidently, an isolate symbiotic supplementation is not enough to counterbalance the dysbiotic state continuously fostered by the urea colonic influx. A harder strategy is likely necessary, and the results we observed during the overlapping period between the symbiotic supplementation and the DVB-PVPexperimental treatment seem to support this interpretation and justify the experimentation of this combined approach for longer periods or for repeated cycles. Adsorption relies on the direct binding of solutes to sorbent materials contained within a cartridge, which depends on the sorbent-solute chemical affinity. One of the main drawbacks of extracorporeal blood purification techniques (i.e., cut-off membranes, high-volume hemofiltration) is the loss of nutrients, such as albumin, useful bioactive molecules, and drugs, therefore, minimizing unwanted molecules loss is an important challenge for sorbent materials research [45]. Indeed, the two resins under investigation also differed in albumin adsorption, with greater adsorption by the DVB-PVP resin. Although the maximum loss with DVB-PVP resin in vitro was about 14%, the in vivo albumin-leaking, due to the use of three consecutive HD sessions with the DVB-PVP cartridge, in both symbiotic/placebo-treated groups, was around 8%, an accepted albumin loss, which could be considered remaining in the normal range concentration [37]. The DVB-PVP cartridge here investigated was able to modulate hydrophobic molecules up to a molecular weight of 60 kDa, which are involved in various critical pathologies, and this ability is widely observed in the literature [24; 25; 46]. Its capability to remove albumin (65-70 kDa), as well as other adsorbents and other proteins from the blood, has not been properly investigated yet. In the literature, [PERSON] and coworkers [47] showed a limited albumin loss from baseline after the treatments, indicating that the device had no significant impact on these values.