Efficacy of Divinylbenzenic Resin in Removing Indoxyl Sulfate and P-Cresol Sulfate in Hemodialysis Patients: Results From an In Vitro Study and An In Vivo Pilot Trial (xuanro4-Nature 3.2).

Maria Teresa Rocchetti,Loreto Gesualdo,Vanessa Galleggiante,Carmela Cosola,Giuseppe Dalfino,Giuseppe Stefano Netti,Stefania Magnani,Roberto Corciulo,Letizia Scandiffio,Ighli Di Bari,Mauro Atti

doi:10.3390/toxins12030170

Maria Teresa Rocchetti, Loreto Gesualdo + Show 9 more

Open Access

https://doi.org/10.3390/toxins12030170

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Abstract

High serum levels of microbiota-derived uremic toxins, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), are associated with chronic kidney disease (CKD) progression and cardiovascular complications. IS and PCS cannot be efficiently removed by conventional hemodialysis (HD), due to their high binding affinity for albumin. This study evaluates the efficacy of a divinylbenzene-polyvinylpyrrolidone (DVB-PVP) cartridge and a synbiotic to reduce uremic toxins in HD patients. First, the in vitro efficacy of DVB-PVP in adsorbing IS and PCS was evaluated. Second, a randomized, placebo-controlled pilot study in HD patients was carried out to establish whether the administration of a synbiotic, either individually and in association with DVB-PVP-HD, could reduce the production of uremic toxins. In vitro data showed that DVB-PVP resin removed a mean of 56% PCS and around 54% IS, after 6 h of perfusion. While, in the in vivo study, the DVB-PVP cartridge showed its adsorbing efficacy only for IS plasma levels. The combination of synbiotic treatment with DVB-PVP HD decreased IS and PCS both at pre- and post-dialysis levels. In conclusion, this study provides the first line of evidence on the synergistic action of gut microbiota modulation and an innovative absorption-based approach in HD patients, aimed at reducing plasma levels of IS and PCS.

Highlights

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]
Some trials carried out with HD patients attempted to lower the production rates of microbial-derived PBUTs, acting on microbiota modulation through probiotic [27,28,29], prebiotics [30,31], and synbiotics [32], with contrasting results. These premises represent the rationale for the NATURE study, in which we aimed to use a double-edged approach to the reduction of PBUTs in HD patients, consisting in the upstream reduction reduction in their production at colonic level, and in the downstream improvement in the efficacy of their removal by the treatment
Routinely used for many years in drug intoxication [33] and poisoning, have been more recently employed in other clinical application, such as sepsis [34,35], acute kidney injury [36], and, lately, to remove molecules not cleared by HD, such as PBUTs [20,21,37,38,39]

Summary

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]. 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.

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