Abstract: TH-PO360
Using Binding Competitors of Albumin to Promote the Removal of Protein-Bound Uremic Toxins in Hemodialysis: Proof of Concept and Screening of Candidates
Session Information
- Dialysis: Dialysate and Clearance
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Dialysis
- 701 Dialysis: Hemodialysis and Frequent Dialysis
Authors
- Florens, Nans, Hospices Civils de Lyon, Lyon, France
- Yi, Dan, CarMeN, INSERM u1060, INSA LYON, VILLEURBANNE, France
- Soulère, Laurent, INSA LYON, Villeurbanne, France
- Juillard, Laurent, Hospices Civils de Lyon, Lyon, France
- Soulage, Christophe O., CarMeN, INSERM u1060, INSA LYON, VILLEURBANNE, France
Background
Protein-bound uremic toxins (PBUT) remain a concerning burden as their removal in hemodialysis is limited by their strong interaction with albumin. Despite interesting animal data, the limitation of their intestinal production is disappointing. By enhancing their circulating free-fraction during hemodialysis, the use of binding competitors could be undertaken. The aim of this work was to evaluate the displacing capabilities of some selected solutes and to identify potential candidates for an in vivo development.
Methods
Displacement capacity of a fluorescent probe (dansylsarcosine) specific to Sudlow’s site II on albumin was tested in spectrofluorimetry. Displacement capacity was then expressed as a concentration displacer/albumin ratio. Short chain fatty acids were provided by Sigma-Aldrich. The selection of potential candidate solutes was realized by an in-silico screening (virtual screening and docking) of 12,055 compounds from Asinex chemotech library. The effect on the free-fraction of indoxyl-sulfate (IS) was tested after an addition of a 1mM solution of octanoic C8 in a solution of bovine serum albumin previously incubated with a solution of IS.
Results
Among the short chain fatty acids tested, C8 and C10 were the more prone to displace dansylsarcosine from site II of albumin (75% for C8 ; displacer/albumin ratio of 5). In silico sreening identify 10 potential candidates among which N-phelyl-glycine and N-phenyl-N-benzenesulfonyl glycine (PBSG) were the best candidates. Indeed, the displacement obtained was roughly 60% for a displacer/albumin ratio between 50 and 250. The addition of a 1mM solution of C8 to a solution of bovine serum albumin permitted an increase of 22% of the free-fraction of IS (p<0.05).
Conclusion
C8 permitted a significant increase in the free fraction of IS in vitro. Nevertheless, significant concentrations of short chain fatty acids can lead to a significant hemolysis. Hence, we identified two interesting solutes that could be interesting to promote the removal of PBT: N-phenyl-glycine and PBSG. Those hydrophilic solutes need to prove their safety under physiological conditions and their effects on other compounds bound onto site II of albumin need further investigations.