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.

Keywords: OAT; OCT; chronic kidney disease (CKD); protein-bound uremic toxins.

Figure 1

Degrees of decreased kidney function, adapted from [1].

Figure 2

Chemical structures of anionic and cationic UTs (adapted from [6]).

Figure 3

HAS structure. The primary binding sites for anionic, neutral, and cationic ligands are commonly referred to as Sudlow’s sites I and II. In general, bulky heterocyclic anion ligands generally bind to Sudlow’s site I (or the warfarin site), whereas Sudlow’s site II (or the indole-benzodiazepine site) ligands are aromatic and can be either neutral or bear a negative charge located peripherally on the molecule (adapted from [27]).

Figure 4

UTs-induced ROS production.

Figure 5

(a) nephron structure; (b) organic anionic transporter’s structure.

Figure 6

The roles of transporters in the human kidney.

Figure 7

IS promotes the progression of CKD.

Figure 8

Pathological role of organic anion transporters (OATs) in the progression of uremia, atherosclerosis, and kidney bone disease.

Figure 9

OAT- or OCT-mediated cellular transport of anionic and cationic uremic toxins (adapted from [6]).

Figure 10

IS and PCS displacement in uremic plasma by furosemide (FUR), tryptophan (TRP), and IBU (left), and the IBU and FUR dosage effect in IS displacement (right), both determined in static RED assays [93].

Figure 11

Human whole blood experiments with a competitive binding strategy showing IS removal (left) and urea removal (right) (adapted from [93]).

Figure 12

Schematic concept of the dialyzer used in a previous work by Madero et al. (adapted from [94]).