## 1 Introduction  
Protein-bound uremic toxins (PBUTs), such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS), accumulate in chronic kidney disease (CKD), especially in patients with end-stage renal disease (ESRD) [1; 2; 3]. IS and PCS, derived from the gut microbiota metabolism of dietary amino acids, tryptophan, and tyrosine, are absorbed by the gastrointestinal tract and sulfated in the liver, then circulate in blood non-covalently and competitively bind to albumin and are actively excreted in urine via the basolateral organic anion transporters in the renal tubules [4]. The circulating levels of IS and PCS increase with the progression of renal failure in CKD, reaching their maximal concentration in patients undergoing hemodialysis (HD) treatment, where higher levels predict poor clinical outcomes [5; 6] even in elderly HD patients [7]. These microbial-derived metabolites are emerging as non-traditional cardiovascular risk factors in CKD [8], as evidenced by meta-analyses and cohort studies that associate them to all-cause or cardiovascular mortality [7; 9; 10]. Compared to the classical uremic markers, such as urea and creatinine, which are far more efficiently removed by dialysis treatment [11], IS and PCS are not sufficiently removed because of their high binding affinity to albumin, which makes only a low (2-5%) [1] free fraction available to diffusion in the dialysate. Therefore, PBUTs represent a challenge for extracorporeal renal replacement strategies because only the unbound solute can pass through conventional dialysis membranes. Despite the progress in dialysis treatment, the reduction rate (RR) of total IS (protein-bound and unbound IS) with standard HD remains lower than 35% [1; 11; 12], unless longer dialysis sessions, raising the dialysate flow and dialyzer size [13; 14; 15], or advanced synthetic high-flux membranes [16] are used for extracorporeal renal replacement therapy. In these cases, the RRs of total IS hardly reach values of 50% (40% for total PCS), which is still not enough as its plasma levels often remain highly elevated after HD [13; 16; 17]. Moreover, IS and PCS circulating levels rapidly rise again before the following dialysis session [18]; therefore, a therapeutic strategy, synergistically acting both upstream, reducing the production of uremic toxins, and downstream, increasing their removal, is expected to be advantageous. In recent years, the use of sorbents in hemoperfusion (HP) or plasma perfusion has become common, mostly in combination with other blood purification techniques [19]. Adsorption is considered a complementary mechanism for solute removal, due to the intrinsic capability of sorbents to bind molecules based on chemical affinity rather than membrane permeability, sieving coefficient, and the molecular weight cut-off, typical mechanisms influencing diffusion and convection. In HP, blood circulates through a cartridge containing the solid sorbent material. In clinical practice, several new sorbents have been proposed to specifically remove target molecules, including PBUTs [20; 21]. The in vivo efficacy of sorbents to remove the uremic toxins predicted by in vitro studies is still debated [21]. In this field, the most promising adsorbent materials are based on divinylbenzene coated with polyvinylpyrrolidone (DVB-PVP) or cellulose with hexadecyl chains for their high hydrophobic nature and biocompatibility, making them appropriate for the direct use in whole blood. These materials have been reported to remove molecules with chemical characteristics similar to PBUTs, such as albumin-bound bilirubin [22; 23] or hydrophobic cytokines [24; 25], in several clinical settings. These compounds have a hydrophobic characteristic similar to the microbial-derived metabolites, justifying the rationale for the use of DVB-PVP or cellulosic resins for the absorption of either IS and PCS.