Adsorption of Protein‐Bound Uremic Toxins Through Direct Hemoperfusion With Hexadecyl‐Immobilized Cellulose Beads in Patients Undergoing Hemodialysis

Abstract

An accumulation of protein-bound uremic toxins (PBUTs) is one of major reasons for development of uremia-related complications. We examined the PBUT removal ability of a hexadecyl-immobilized cellulose bead (HICB)-containing column for patients undergoing hemodialysis. Adsorption of indoxyl sulfate (IS), a representative PBUT, to HICBs was examined in vitro. The HICB column was used in patients undergoing hemodialysis for direct hemoperfusion with a regular hemodialyzer. The serum IS, indole acetic acid (IAA), phenyl sulfate (PhS), and p-cresyl sulfate (PCS) levels were measured before and after passing the column. HICBs adsorbed protein-free (free) IS in a dose-and time-dependent manner in vitro (55.4 6 1.4% adsorption of 1 millimolar, 251 mg/mL, IS for 1 h). In clinical studies, passing the HICB-containing column decreased the serum level of free IS, IAA, PhS, and PCS levels significantly (by 34.4 6 30.0%, 34.8 6 25.4%, 28.4 6 18.0%, and 34.9 6 22.1%, respectively), but not protein-bound toxins in maintenance hemodialysis patients. HICBs absorbed some amount of free PBUTs, but the clinical trial to use HICB column did not show effect to reduce serum PBUTs level in hemodialysis patients. Adsorption treatment by means of direct hemoperfusion with regular hemodialysis may become an attractive blood purification treatment to increase PBUT removal when more effective materials to adsorb PBUTs selectively will be developed. Key Words: Protein-bound uremic toxins-Direct hemoperfusion-Hexadecylimmobilized cellulose beads-AdsorptionHemodialysis.An accumulation of protein-bound uremic toxins (PBUTs) is associated with various diseases related to chronic kidney disease (CKD), including cardiovascular diseases (1,2). The circulating levels of PBUTs, such as indoxyl sulfate (IS), p-cresyl sulfate (PCS), and indole acetic acid (IAA), increase with the progress of CKD, and the high blood levels of these toxins are related to all-cause or cardiovascular mortality in patients with CKD, especially those undergoing dialysis treatment (3-5). Recent progress in dialysis treatment has improved the removal of water-soluble small-and middle-molecular-weight molecules; however, the removal of PBUTs is not enough because of their high binding property to albumin, which is difficult to remove with diffusion in hemodialysis treatment (6). For example, the proteinbinding rate of IS was reported to be 98%, and the reduction rate (RR) with regular hemodialysis of total including both protein-bound and unbound IS was only from 32% to 50% (7-9). Some amount of PBUTs are removed by a regular hemodialysis;

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)

“…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].…”

Effect of hemoperfusion with hexadecyl-immobilized cellulose beads on myocardial fatty acid imaging in hemodialysis patients: a case series study

“…HICBs adsorb free protein-bound uremic toxins (e.g., free indoxyl sulfate (IS) and free p-cresyl sulfate (PCS)) that are involved in oxidative stress [3]. IS has been shown to induce the production of reactive oxygen species in vitro [28][29][30].…”

“…Hexadecyl-immobilized porous cellulose beads (HICBs), with an appropriate pore size and a mean diameter of 460 mm and contained within a column (Lixelle; Kaneka Medix Co), were originally designed to selectively adsorb β2-microglobulin (β2-MG) through hydrophobic interactions [1]. Several reports have suggested that in addition to β2-MG, the Lixelle column also removes several inflammatory cytokines and free protein-binding uremic toxins (PBUTs) [2,3]. Dialysis patients are in a chronic, persistently activated inflammatory state, as demonstrated by both elevated inflammatory markers and proinflammatory cytokines, such as interleukin-6 (IL-6) [4].…”

Enhanced Removal of Protein-Bound Uremic Toxins Using Displacers

“…These can be applied at the serum or the dialysate side depending on the carrier. For example, using a hexadecyl-immobilized cellulose bead-containing column for hemoperfusion coupled to a regular hemodialyzer, serum levels of free IS, PCS, indole acetic acid, and phenyl sulfate were reduced by about one third, but total PBUT level did not change (4). Adsorptive beads have been added to the dialysate site (5).…”