Exploring Protein Binding of Uremic Toxins in Patients with Different Stages of Chronic Kidney Disease and during Hemodialysis

Abstract

As protein binding of uremic toxins is not well understood, neither in chronic kidney disease (CKD) progression, nor during a hemodialysis (HD) session, we studied protein binding in two cross-sectional studies. Ninety-five CKD 2 to 5 patients and ten stable hemodialysis patients were included. Blood samples were taken either during the routine ambulatory visit (CKD patients) or from blood inlet and outlet line during dialysis (HD patients). Total (CT) and free concentrations were determined of p-cresylglucuronide (pCG), hippuric acid (HA), indole-3-acetic acid (IAA), indoxyl sulfate (IS) and p-cresylsulfate (pCS), and their percentage protein binding (%PB) was calculated. In CKD patients, %PB/CT resulted in a positive correlation (all p < 0.001) with renal function for all five uremic toxins. In HD patients, %PB was increased after 120 min of dialysis for HA and at the dialysis end for the stronger (IAA) and the highly-bound (IS and pCS) solutes. During one passage through the dialyzer at 120 min, %PB was increased for HA (borderline), IAA, IS and pCS. These findings explain why protein-bound solutes are difficult to remove by dialysis: a combination of the fact that (i) only the free fraction can pass the filter and (ii) the equilibrium, as it was pre-dialysis, cannot be restored during the dialysis session, as it is continuously disturbed.

Interaction of human serum albumin with uremic toxins: a thermodynamic study

“…8,34 Hence, a comparison of the thermodynamic data of PhAA bearing a weak acidic group (COO À ) with the ones obtained from IDS can reveal details of the ionic interaction and its relation to toxin binding.…”

“…Well studied toxins and their interaction to HSA are p-cresyl sulfate (PCS), hippuric acid (HA) and indoxyl sulfate (IDS). 7,8 Bound to HSA, these toxins will inhibit the transport ability of the protein and may lead to structural modications. 4,5,9 Most toxins are found to interact with either one or both of the hydrophobic binding sites Sudlow I and II of HSA located in the subdomains IIA and IIIA.…”

Aryl Hydrocarbon Receptor Activation in Chronic Kidney Disease: Role of Uremic Toxins

“…In CKD patients, these compounds tend to accumulate in the body fluids once they are protein-bound. Therefore, they can neither be excreted through urine nor be efficiently eliminated by dialysis modalities [5] . These retained compounds are often referred to as uremic toxins because they are cytotoxic, negatively impact biological functions and exert pathological effects on immune systems, kidney, blood vessels and heart [21] .…”

“…Uremic toxins cannot be excreted in urine in chronic kidney disease (CKD) patients or efficiently eliminated by common dialysis modalities; thus, they accumulate [5] . As a result, tryptophan metabolism-derived uremic toxins are able to activate AhR and, therefore, chronically stimulate oxidative stress and inflammation [4] .…”

Is there a relationship between tryptophan dietary intake and plasma levels of indoxyl sulfate in chronic kidney disease patients on hemodialysis?

“…15 During dialysis the levels of these toxins increase, since dialysis cannot efficiently remove them. 16 IS seems to promote the progression of CKD because of its pro-fibrotic effects on glomeruli, 17,18 and for its role in the induction of endothelial dysfunction, vascular 19 smooth muscle cell proliferation, and atherosclerosis;…”