Improved Dialysis Removal of Protein-Bound Uraemic Toxins with a Combined Displacement and Adsorption Technique

Shi, Yuanyuan; Tian, Hui; Wang, Yifeng; Shen, Yanbin; Zhu, Qiuyu; Ding, Feng

doi:10.1159/000518065

Cited by 11 publications

(10 citation statements)

References 53 publications

(109 reference statements)

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“…In silico analysis informed us that competitive binding during HD significantly outperforms other state-of-the-art dialysis therapies, namely pre-and postdilution hemodiafiltration and ideal membrane adsorption (Figure 6) [22]. These in silico findings are qualitatively validated by Shi et al 2021, who compared binding competition and adsorption (by albumin dialysis) in pre-clinical uremic rat models and observed that binding competition outperformed adsorption [20].…”

Section: In Silico Evidencementioning

confidence: 60%

“…Binding competition outperformed albumin dialysis and improved IS and pCS removal by approximately 10-fold in comparison to conventional 4 h HD. Notably, combining binding competition and albumin dialysis further improved the removal of putative PBUTs [20]. This study indirectly underscores the fact that protein binding is the primary resistance for PBUTs removal.…”

Section: Clinical Evidencementioning

confidence: 60%

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Removal of Protein-Bound Uremic Toxins Using Binding Competitors in Hemodialysis: A Narrative Review

Maheshwari

Thijssen

Kotanko

2021

Toxins

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Removal of protein-bound uremic toxins (PBUTs) during conventional dialysis is insufficient. PBUTs are associated with comorbidities and mortality in dialysis patients. Albumin is the primary carrier for PBUTs and only a small free fraction of PBUTs are dialyzable. In the past, we proposed a novel method where a binding competitor is infused upstream of a dialyzer into an extracorporeal circuit. The competitor competes with PBUTs for their binding sites on albumin and increases the free PBUT fraction. Essentially, binding competitor-augmented hemodialysis is a reactive membrane separation technique and is a paradigm shift from conventional dialysis therapies. The proposed method has been tested in silico, ex vivo, and in vivo, and has proven to be very effective in all scenarios. In an ex vivo study and a proof-of-concept clinical study with 18 patients, ibuprofen was used as a binding competitor; however, chronic ibuprofen infusion may affect residual kidney function. Binding competition with free fatty acids significantly improved PBUT removal in pre-clinical rat models. Based on in silico analysis, tryptophan can also be used as a binding competitor; importantly, fatty acids or tryptophan may have salutary effects in HD patients. More chemoinformatics research, pre-clinical, and clinical studies are required to identify ideal binding competitors before routine clinical use.

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Section: In Silico Evidencementioning

confidence: 60%

Section: Clinical Evidencementioning

confidence: 60%

Removal of Protein-Bound Uremic Toxins Using Binding Competitors in Hemodialysis: A Narrative Review

Maheshwari

Thijssen

Kotanko

2021

Toxins

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“…The same rationale applies to protein-bound uremic toxins. An in vitro model demonstrated that the removal of indoxyl sulfate, p-cresyl sulfate, and hippuric acid was higher with a dialysate containing albumin when compared to standard bicarbonate dialysate [72]. Clinical trials with this strategy are still lacking.…”

Section: Adsorptionmentioning

confidence: 99%

Rationale for a New Classification of Solutes of Interest in Chronic Kidney Disease and Hemodialysis

et al. 2023

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A hallmark of chronic kidney disease is the retention of solutes that normally are eliminated by the kidneys. The current classification defines uremic toxins based on molecular weight and protein affinity. The retention of solutes is already detected in the early stages of the disease when patients are pauci-symptomatic or asymptomatic but the role of therapies to retard the loss of kidney function in patients with chronic kidney disease (e.g., modulators of the renin-angiotensin-aldosterone system, sodium-glucose cotransporter inhibitors) in reducing uremic toxins is poorly understood. Most of the research evaluating the impact of therapies to lower serum concentrations of those toxic compounds is carried out in patients with kidney failure already undergoing kidney replacement therapy. The removal of those molecules relies in physicochemical mass transfer phenomena, i.e., adsorption, diffusion, and convection. In the past 2 decades, the rise and broad adoption of blood purification strategies with enhanced convective properties, such as high-volume online hemodiafiltration and expanded hemodialysis, considerably amplified the ability to mechanically extract middle molecules (molecular weight >0.5 kDa) from the blood compartment. Nonetheless, the classification of uremic toxins has not evolved in parallel with dialysis advancements. Mounting evidence demonstrates the link between middle molecules with uremic symptoms, cardiovascular and mortality risks. An urgent need for updating the classification exists. Defining the causative relationship between specific solutes and specific clinical outcomes will promote the development of targeted therapies. In parallel, the inclusion of new pertinent dimensions to the classification like the influence of new dialysis membranes, sorbents, and intestinal chelators in the concentration of uremic toxins would improve the understanding of the pathogenesis of chronic kidney disease, setting the pace for future research in nephrology.

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“…Second, we propose an approach that combines displacement of CMPF using an exogenous binding competitor to increase its free fraction followed by adsorption (Figure 4C). 16 Previous clinical proof-of-concept studies have demonstrated the utility of the displacer concept to enhance the dialytic removal of protein-bound uremic solutes. 17 Third, albumin dialysis, a method used primarily in patients with liver failure to remove .…”

Section: Jedi1 Jedi1mentioning

confidence: 99%

The Piezo1 hypothesis of renal anemia

et al. 2022

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Erythropoietin deficiency is an extensively researched cause of renal anemia. The etiology and consequences of shortened red blood cell (RBC) life span in chronic kidney disease (CKD) are less well understood. Traversing capillaries requires RBC geometry changes, a process enabled by adaptions of the cytoskeleton. These changes are mediated by transient activation of the mechanosensory Piezo1 channel, resulting in calcium influx. Importantly, prolonged Piezo1 activation shortens RBC life span, presumably through activation of calcium‐dependent intracellular pathways triggering RBC death. Two Piezo1‐activating small molecules, Jedi1 and Jedi2, share remarkable structural similarities with 3‐carboxy‐4‐methyl‐5‐propyl‐2‐furanpropanoic acid (CMPF), a uremic retention solute cleared by the healthy kidney. We hypothesize that in CKD the accumulation of CMPF leads to prolonged activation of Piezo1 (similar in effect to Jedi1 and Jedi2), thus reducing RBC life span. This hypothesis can be tested through bench experiments and, ultimately, by studying the effect of CMPF removal on renal anemia.

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Improved Dialysis Removal of Protein-Bound Uraemic Toxins with a Combined Displacement and Adsorption Technique

Cited by 11 publications

References 53 publications

Removal of Protein-Bound Uremic Toxins Using Binding Competitors in Hemodialysis: A Narrative Review

Removal of Protein-Bound Uremic Toxins Using Binding Competitors in Hemodialysis: A Narrative Review

Rationale for a New Classification of Solutes of Interest in Chronic Kidney Disease and Hemodialysis

The Piezo1 hypothesis of renal anemia

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