In silico comparison of protein-bound uremic toxin removal by hemodialysis, hemodiafiltration, membrane adsorption, and binding competition

Vaibhav Maheshwari,Xia Tao,Doris H Fuertinger,Stephan Thijssen,Peter Kotanko,Franz Kappel

doi:10.1038/s41598-018-37195-1

Abstract

Protein-bound uremic toxins (PBUTs) are poorly removed during hemodialysis (HD) due to their low free (dialyzable) plasma concentration. We compared PBUT removal between HD, hemodiafiltration (HDF), membrane adsorption, and PBUT displacement in HD. The latter involves infusing a binding competitor pre-dialyzer, which competes with PBUTs for their albumin binding sites and increases their free fraction. We used a mathematical model of PBUT/displacer kinetics in dialysis comprising a three-compartment patient model, an arterial/venous tube segment model, and a dialyzer model. Compared to HD, improvements in removal of prototypical PBUTs indoxyl sulfate (initial concentration 100 µM, 7% free) and p-cresyl sulfate (150 µM, 5% free) were: 5.5% and 6.4%, respectively, for pre-dilution HDF with 20 L replacement fluid; 8.1% and 9.1% for post-dilution HDF 20 L; 15.6% and 18.3% for pre-dilution HDF 60 L; 19.4% and 22.2% for complete membrane adsorption; 35.0% and 41.9% for displacement with tryptophan (2000 mg in 500 mL saline); 26.7% and 32.4% for displacement with ibuprofen (800 mg in 200 mL saline). Prolonged (one-month) use of tryptophan reduces the IS and pCS time-averaged concentration by 28.1% and 29.9%, respectively, compared to conventional HD. We conclude that competitive binding can be a pragmatic approach for improving PBUT removal.

Highlights

Protein-bound uremic toxins (PBUTs) have been implicated in numerous deleterious effects in chronic kidney disease (CKD) patients as well as in end-stage renal disease (ESRD) patients[1]
Our model simulations suggest that binding competition in HD extracorporeal circuit substantially improves the PBUTs removal over conventional HD, HDF, and membrane adsorption
This is the first report to provide a comparative assessment of PBUTs removal in standard HD, pre-dilution HDF 20 L and 60 L, post-dilution HDF 20 L, ideal membrane adsorption, and binding competition in HD where competitor drugs were tryptophan or ibuprofen

Summary

Introduction

Protein-bound uremic toxins (PBUTs) have been implicated in numerous deleterious effects in chronic kidney disease (CKD) patients as well as in end-stage renal disease (ESRD) patients[1]. Pre-dialysis concentration of IS and pCS have been found to be as much as 116-fold and 41-fold higher, respectively, than in the age-matched healthy controls, while concentrations of unbound marker toxins, urea and creatinine, were only 5- and 13-fold higher, respectively[5]. Both IS and pCS have been causally associated with pathophysiological events in HD patients such as cellular dysfunction, oxidative stress, cell senescence, to name a few[1].

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Results

Conclusion