Interaction of Human Serum Albumin with Uremic Toxins: The Need of New Strategies Aiming at Uremic Toxins Removal

Abstract

Chronic kidney disease (CKD) is acknowledged worldwide to be a grave threat to public health, with the number of US end-stage kidney disease (ESKD) patients increasing steeply from 10,000 in 1973 to 703,243 in 2015. Protein-bound uremic toxins (PBUTs) are excreted by renal tubular secretion in healthy humans, but hardly removed by traditional haemodialysis (HD) in ESKD patients. The accumulation of these toxins is a major contributor to these sufferers’ morbidity and mortality. As a result, some improvements to dialytic removal have been proposed, each with their own upsides and drawbacks. Longer dialysis sessions and hemodiafiltration, though, have not performed especially well, while larger dialyzers, coupled with a higher dialysate flow, proved to have some efficiency in indoxyl sulfate (IS) clearance, but with reduced impact on patients’ quality of life. More efficient in removing PBUTs was fractionated plasma separation and adsorption, but the risk of occlusive thrombosis was worryingly high. A promising technique for the removal of PBUTs is binding competition, which holds great hopes for future HD. This short review starts by presenting the PBUTs chemistry with emphasis on the chemical interactions with the transport protein, human serum albumin (HSA). Recent membrane-based strategies targeting PBUTs removal are also presented, and their efficiency is discussed.

A Novel Strategy for Enhanced Sequestration of Protein-Bound Uremic Toxins Using Smart Hybrid Membranes

“…However, other low molecular compounds, known as protein-bound uremic toxins (PBUTs), are responsible for the most severe CKD complications such as cardiorenal syndrome [ 4 ] and chronic ischemic heart disease [ 5 ]. This is the case of indoxyl sulfate (IS) and p -cresyl sulfate (pCS), whose increased levels have been associated with oxidative stress and enhanced expression of inflammatory genes, leading to high hospitalization and mortality rates [ 6 , 7 , 8 ]. Free PBUTs, which are not bound to proteins, are easily removed by commercial HD membranes by size exclusion, but their high affinity for plasma proteins, especially for human serum albumin (HSA), preclude its removal using the currently available systems.…”

Improving Structural Homogeneity, Hydraulic Permeability, and Mechanical Performance of Asymmetric Monophasic Cellulose Acetate/Silica Membranes: Spinodal Decomposition Mix

“…Polymeric membranes account for the largest market share in membrane filtration technology, particularly in terms of water purification and the desalination processes [ 1 , 2 ]. Likewise, the emerging artificial organ technology focuses on the design and development of novel hemocompatible polymeric membranes to assist the physical and chemical functions of failed organs, such as lungs and kidneys [ 3 , 4 , 5 , 6 ]. Cellulose acetate (CA), a natural biodegradable thermoplastic polymer derived from a low-cost and renewable source, stands out for its large availability and respect for the environment.…”

Adsorption- and Displacement-Based Approaches for the Removal of Protein-Bound Uremic Toxins

“…HSA is the most abundant protein in blood plasma and, because of its extraordinary ligand binding capacity, is responsible for the transport of a wide variety of pharmaceutical drugs throughout the body [ 47 , 48 ]. As mentioned before, the HSA primary binding sites for the PBUTs IS, pCS, IAA and HA is Sudlow’s site II, whereas for CMPF is Sudlow’s site I [ 3 , 29 ]. The HSA-PBUT association constants (K a ) for IS, pCS, IAA, HA, and CMPF are 0.98 × 10 5 M −1 , 1.0 × 10 5 M −1 , 2.1 × 10 5 M −1 , 0.1 × 10 5 M −1 , and 130.5 × 10 5 M −1 , respectively [ 49 , 50 ].…”

“…Other PBUTs such as hippuric acid (HA), indole-3-acetic acid (IAA), and 3-carboxyl4-methil-5-propyl-furanpropionic acid (CMPF), have binding percentages of 48%, 94%, and ~100%, respectively [ 25 ]. The primary binding sites for these PBUTs are Sudlow’s site II of the HSA molecule, with the exception of CMPF which binds to site I [ 3 , 29 ].…”