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Toxins
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New Strategies for the Reduction of Uremic Toxins
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New Strategies for the Reduction of Uremic Toxins

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Uremic Toxins".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 50001

Special Issue Editor

Dr. Maria Teresa Rocchetti

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Guest Editor
Applied Biology - Department of Clinical and Experimental Medicine, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy
Interests: biomarkers of CKD; uremic toxins; microbiota; probiotics; proteomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

The accumulation of organic waste products, i.e., so-called uremic toxins, that are normally cleared by the kidneys characterizes chronic kidney disease (CKD). First of all, along with a number of known and unknown toxic metabolites, urea have the potential to dysregulate cellular functions in kidney and other organs when patients suffer from an illness known as uremia. It is increasingly evident that uremic toxins influence nontraditional risk factors, such as inflammation and endothelial dysfunction, contributing to cardiovascular (CV) damage in CKD. Particularly, protein-bound uremic toxins seem to play an increasing role in the incidence of CV disease in CKD, as well as in blood pressure regulation and hypertension. This is due to the high binding affinity of these metabolites to serum proteins, which makes them not efficently removable via conventional hemodialysis and causes their progressive accumulation in CKD patients, leading to disease progression and resulting in organ damage. Indeed, in the general population, death from CV disease accounts for approximately one in 1000 people per year (6%–13% of all deaths), whereas among CKD patients, it accounts for 59 in 1000 people per year (26% of total mortality). Therefore, strategies aimed at lowering uremic toxins are strongly desirable, in order to reach clinical benefit in terms of slowing the progression of CKD and preventing CV disease.

Dr. Maria Teresa Rocchetti
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • uremic toxins
  • chronic kidney disease
  • cardiovascular risk
  • hemodialysis
  • gut microbiota
  • sorbents
  • synbiotics
  • indoxyl sulfate
  • p-cresyl sulfate
  • trimethylamine-N-Oxide

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Published Papers (16 papers)

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Editorial

Jump to: Research, Review, Other

3 pages, 218 KiB  
Editorial
New Strategies for the Reduction of Uremic Toxins: How Much More We Know
by Maria Teresa Rocchetti
Toxins 2021, 13(12), 837; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13120837 - 24 Nov 2021
Viewed by 1764
Abstract
The importance of uremic toxin (UTx) removal in chronic kidney disease (CKD) is an emerging topic in the literature, widely recognized over time as a strategy to slow-down the disease progression towards end-stage renal disease and, consequentely, the occurence of deleterious effects on [...] Read more.
The importance of uremic toxin (UTx) removal in chronic kidney disease (CKD) is an emerging topic in the literature, widely recognized over time as a strategy to slow-down the disease progression towards end-stage renal disease and, consequentely, the occurence of deleterious effects on cardiovascular (CV) system [...] Full article
(This article belongs to the Special Issue New Strategies for the Reduction of Uremic Toxins)

Research

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12 pages, 1915 KiB  
Article
Towards an Algorithm-Based Tailored Treatment of Acute Neonatal Hyperammonemia
by Sunny Eloot, Jonathan De Rudder, Patrick Verloo, Evelyn Dhont, Ann Raes, Wim Van Biesen and Evelien Snauwaert
Toxins 2021, 13(7), 484; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13070484 - 13 Jul 2021
Cited by 2 | Viewed by 2724
Abstract
Acute neonatal hyperammonemia is associated with poor neurological outcomes and high mortality. We developed, based on kinetic modeling, a user-friendly and widely applicable algorithm to tailor the treatment of acute neonatal hyperammonemia. A single compartmental model was calibrated assuming a distribution volume equal [...] Read more.
Acute neonatal hyperammonemia is associated with poor neurological outcomes and high mortality. We developed, based on kinetic modeling, a user-friendly and widely applicable algorithm to tailor the treatment of acute neonatal hyperammonemia. A single compartmental model was calibrated assuming a distribution volume equal to the patient’s total body water (V), as calculated using Wells’ formula, and dialyzer clearance as derived from the measured ammonia time–concentration curves during 11 dialysis sessions in four patients (3.2 ± 0.4 kg). Based on these kinetic simulations, dialysis protocols could be derived for clinical use with different body weights, start concentrations, dialysis machines/dialyzers and dialysis settings (e.g., blood flow QB). By a single measurement of ammonia concentration at the dialyzer inlet and outlet, dialyzer clearance (K) can be calculated as K = QB∙[(Cinlet − Coutlet)/Cinlet]. The time (T) needed to decrease the ammonia concentration from a predialysis start concentration Cstart to a desired target concentration Ctarget is then equal to T = (−V/K)∙LN(Ctarget/Cstart). By implementing these formulae in a simple spreadsheet, medical staff can draw an institution-specific flowchart for patient-tailored treatment of hyperammonemia. Full article
(This article belongs to the Special Issue New Strategies for the Reduction of Uremic Toxins)
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21 pages, 3947 KiB  
Article
An Innovative Synbiotic Formulation Decreases Free Serum Indoxyl Sulfate, Small Intestine Permeability and Ameliorates Gastrointestinal Symptoms in a Randomized Pilot Trial in Stage IIIb-IV CKD Patients
by Carmela Cosola, Maria Teresa Rocchetti, Ighli di Bari, Paola Maria Acquaviva, Valentina Maranzano, Simone Corciulo, Agostino Di Ciaula, Domenica Maria Di Palo, Flavia Maria La Forgia, Sergio Fontana, Maria De Angelis, Piero Portincasa and Loreto Gesualdo
Toxins 2021, 13(5), 334; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13050334 - 05 May 2021
Cited by 27 | Viewed by 3493
Abstract
Proteolytic dysbiosis of the gut microbiota has been recognized as both a typical feature of chronic kidney disease (CKD) and a risk factor for its progression. Blood accumulation of gut-derived uremic toxins (UTs) like indoxyl sulfate (IS) and p-cresyl sulfate (PCS), intestinal permeability [...] Read more.
Proteolytic dysbiosis of the gut microbiota has been recognized as both a typical feature of chronic kidney disease (CKD) and a risk factor for its progression. Blood accumulation of gut-derived uremic toxins (UTs) like indoxyl sulfate (IS) and p-cresyl sulfate (PCS), intestinal permeability and constipation are typical features accompanying CKD progression and triggering chronic inflammation. In order to verify the efficacy of the innovative synbiotic formulation NATUREN G® in modulating the levels of circulating UTs, intestinal permeability and gastrointestinal symptoms, we set up a randomized, single-blind, placebo-controlled, pilot trial in stage IIIb-IV CKD patients and in healthy controls. Two-month administration of the synbiotic resulted in a decrease of free IS, as compared with the placebo-treated arm, only in the CKD group. The other UTs did not significantly change, although different trends in time (increase in the placebo arm and decrease in the synbiotic arm) were observed. Moreover, after supplementation, reduction of small intestinal permeability and amelioration of abdominal pain and constipation syndromes were observed only in the CKD group. The obtained results suggest the specificity of action of NATUREN G® in CKD and justify further validation in a wider study population. Full article
(This article belongs to the Special Issue New Strategies for the Reduction of Uremic Toxins)
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13 pages, 13643 KiB  
Article
The Administration of the Synbiotic Lactobacillus bulgaricus 6c3 Strain, Inulin and Fructooligosaccharide Decreases the Concentrations of Indoxyl Sulfate and Kidney Damage in a Rat Model
by Alonso Jerez-Morales, José S. Merino, Sindy T. Díaz-Castillo, Carlos T. Smith, Jorge Fuentealba, Humberto Bernasconi, Gerson Echeverría and Apolinaria García-Cancino
Toxins 2021, 13(3), 192; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13030192 - 07 Mar 2021
Cited by 11 | Viewed by 2655
Abstract
Indoxyl sulfate (IS) is involved in the progression of chronic kidney disease (CKD) and in its cardiovascular complications. One of the approaches proposed to decrease IS is the administration of synbiotics. This work aimed to search for a probiotic strain capable to decrease [...] Read more.
Indoxyl sulfate (IS) is involved in the progression of chronic kidney disease (CKD) and in its cardiovascular complications. One of the approaches proposed to decrease IS is the administration of synbiotics. This work aimed to search for a probiotic strain capable to decrease serum IS levels and mix it with two prebiotics (inulin and fructooligosaccharide (FOS)) to produce a putative synbiotic and test it in a rat CKD model. Two groups of Sprague-Dawley rats were nephrectomized. One group (Lac) received the mixture for 16 weeks in drinking water and the other no (Nef). A control group (C) included sham-nephrectomized rats. Serum creatinine and IS concentrations were measured using high-performance liquid chromatography with diode array detector (HPLC-DAD). Optical microscopy and two-photon excitation microscopy was used to study kidney and heart samples. The Lac group, which received the synbiotic, reduced IS by 0.8% while the Nef group increased it by 38.8%. Histological analysis of kidneys showed that the Lac group increased fibrotic areas by 12% and the Nef group did it by 25%. The synbiotic did not reduce cardiac fibrosis. Therefore, the putative synbiotic showed that function reducing IS and the progression of CKD in a rat model, but no heart protection was observed. Full article
(This article belongs to the Special Issue New Strategies for the Reduction of Uremic Toxins)
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13 pages, 1632 KiB  
Article
A New Peritoneal Dialysis Solution Containing L-Carnitine and Xylitol for Patients on Continuous Ambulatory Peritoneal Dialysis: First Clinical Experience
by Carmela Rago, Teresa Lombardi, Giorgia Di Fulvio, Lorenzo Di Liberato, Arduino Arduini, José C. Divino-Filho and Mario Bonomini
Toxins 2021, 13(3), 174; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13030174 - 24 Feb 2021
Cited by 19 | Viewed by 2515
Abstract
Peritoneal dialysis (PD) is a feasible and effective renal replacement therapy (RRT) thanks to the dialytic properties of the peritoneal membrane (PM). Preservation of PM integrity and transport function is the key to the success of PD therapy, particularly in the long term, [...] Read more.
Peritoneal dialysis (PD) is a feasible and effective renal replacement therapy (RRT) thanks to the dialytic properties of the peritoneal membrane (PM). Preservation of PM integrity and transport function is the key to the success of PD therapy, particularly in the long term, since the prolonged exposure to unphysiological hypertonic glucose-based PD solutions in current use is detrimental to the PM, with progressive loss of peritoneal ultrafiltration capacity causing technique failure. Moreover, absorbing too much glucose intraperitoneally from the dialysate may give rise to a number of systemic metabolic effects. Here we report the preliminary results of the first clinical experience based on the use in continuous ambulatory PD (CAPD) patients of novel PD solutions obtained through partly replacing the glucose load with other osmotically active metabolites, such as L-carnitine and xylitol. Ten CAPD patients were treated for four weeks with the new solutions. There was good tolerance to the experimental PD solutions, and no adverse safety signals were observed. Parameters of dialysis efficiency including creatinine clearance and urea Kt/V proved to be stable as well as fluid status, diuresis, and total peritoneal ultrafiltration. The promising tolerance and local/systemic advantages of using L-carnitine and xylitol in the PD solution merit further research. Full article
(This article belongs to the Special Issue New Strategies for the Reduction of Uremic Toxins)
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9 pages, 1516 KiB  
Article
pH-Dependent Protein Binding Properties of Uremic Toxins In Vitro
by Suguru Yamamoto, Kenichi Sasahara, Mio Domon, Keiichi Yamaguchi, Toru Ito, Shin Goto, Yuji Goto and Ichiei Narita
Toxins 2021, 13(2), 116; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13020116 - 04 Feb 2021
Cited by 7 | Viewed by 1961
Abstract
Protein-bound uremic toxins (PBUTs) are difficult to remove using conventional dialysis treatment owing to their high protein-binding affinity. As pH changes the conformation of proteins, it may be associated with the binding of uremic toxins. Albumin conformation at pH 2 to 13 was [...] Read more.
Protein-bound uremic toxins (PBUTs) are difficult to remove using conventional dialysis treatment owing to their high protein-binding affinity. As pH changes the conformation of proteins, it may be associated with the binding of uremic toxins. Albumin conformation at pH 2 to 13 was analyzed using circular dichroism. The protein binding behavior between indoxyl sulfate (IS) and albumin was examined using isothermal titration calorimetry. Albumin with IS, and serum with IS, p-cresyl sulfate, indole acetic acid or phenyl sulfate, as well as serum from hemodialysis patients, were adjusted pH of 3 to 11, and the concentration of the free PBUTs was measured using mass spectrometry. Albumin was unfolded at pH < 4 or >12, and weakened interaction with IS occurred at pH < 5 or >10. The concentration of free IS in the albumin solution was increased at pH 4.0 and pH 11.0. Addition of human serum to each toxin resulted in increased free forms at acidic and alkaline pH. The pH values of serums from patients undergoing hemodialysis adjusted to 3.4 and 11.3 resulted in increased concentrations of the free forms of PBUTs. In conclusion, acidic and alkaline pH conditions changed the albumin conformation and weakened the protein binding property of PBUTs in vitro. Full article
(This article belongs to the Special Issue New Strategies for the Reduction of Uremic Toxins)
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16 pages, 1859 KiB  
Article
Varying Protein Levels Influence Metabolomics and the Gut Microbiome in Healthy Adult Dogs
by Eden Ephraim, Chun-Yen Cochrane and Dennis E. Jewell
Toxins 2020, 12(8), 517; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12080517 - 12 Aug 2020
Cited by 31 | Viewed by 5386
Abstract
The optimal ranges of protein for healthy adult dogs are not known. This study evaluated the impact of long-term consumption of foods containing low, medium, and high levels of protein on serum, urine, and fecal metabolites, and gut microbiome in beagles. Following maintenance [...] Read more.
The optimal ranges of protein for healthy adult dogs are not known. This study evaluated the impact of long-term consumption of foods containing low, medium, and high levels of protein on serum, urine, and fecal metabolites, and gut microbiome in beagles. Following maintenance on a prefeed food for 14 days, dogs (15 neutered males, 15 spayed females, aged 2–9 years, mean initial weight 11.3 kg) consumed the low (18.99%, dry matter basis), medium (25.34%), or high (45.77%) protein foods, each for 90 days, in a William’s Latin Square Design sequence. In serum and/or urine, metabolites associated with inflammation (9,10-dihydroxyoctadecanoic acid (DiHOME)), 12,13-DiHOME) and kidney dysfunction (urea, 5-hydroxyindole sulfate, 7-hydroxyindole sulfate, p-cresol sulfate) increased with higher protein levels in food, while one-carbon pathway metabolites (betaine, dimethylglycine, sarcosine) decreased. Fecal pH increased with protein consumed, and levels of beneficial indoles and short-chain fatty acids decreased while branched-chain fatty acids increased. Beta diversity of the fecal microbiome was significantly different, with increased abundances of proteolytic bacteria with higher protein food. Feeding dogs a high amount of protein leads to a shift to proteolytic gut bacteria, higher fecal pH, and is associated with increased levels of metabolites linked with inflammation and kidney dysfunction. Full article
(This article belongs to the Special Issue New Strategies for the Reduction of Uremic Toxins)
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12 pages, 280 KiB  
Article
Prebiotic Therapy with Inulin Associated with Low Protein Diet in Chronic Kidney Disease Patients: Evaluation of Nutritional, Cardiovascular and Psychocognitive Parameters
by Silvia Lai, Sandro Mazzaferro, Maurizio Muscaritoli, Daniela Mastroluca, Massimo Testorio, Adolfo Perrotta, Ylenia Esposito, Maria Carta, Linda Campagna, Marta Di Grado, Cesarina Ramaccini, Sabrina De Leo, Alessandro Galani, Maria Ida Amabile and Alessio Molfino
Toxins 2020, 12(6), 381; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12060381 - 09 Jun 2020
Cited by 12 | Viewed by 3678
Abstract
A relationship between dysbiotic gut microbiome and chronic kidney disease (CKD) has been recently documented; it contributes to CKD-related complications, including cardiovascular disease. Aim: We tested how a low-protein diet (LPD)—with or without oral inulin supplementation as a prebiotic—modulates some inflammatory, atherosclerosis and [...] Read more.
A relationship between dysbiotic gut microbiome and chronic kidney disease (CKD) has been recently documented; it contributes to CKD-related complications, including cardiovascular disease. Aim: We tested how a low-protein diet (LPD)—with or without oral inulin supplementation as a prebiotic—modulates some inflammatory, atherosclerosis and endothelial dysfunction indices and nutritional markers, as well as psychocognitive functions in CKD patients. We conducted a prospective, case–control study on CKD patients on conservative therapy, divided in two groups: the intervention group treated with LPD (0.6 g/kg/day) plus inulin (19 g/day) and a control group treated with LPD without inulin, for six consecutive months. Clinical and hematochemical parameters as well as instrumental, and psychocognitive assessments (by SF-36 survey and MMSE, HAM-D, BDI-II) were recorded in all the participants at baseline (T0), at three months (T1) and at six months (T2). A total of 41 patients were enrolled: 18 in the intervention group and 23 in the control group. At T2, in both groups, we observed a significant reduction of serum nitrogen and phosphorus (p ≤ 0.01) and serum uric acid (p ≤ 0.03), and an improvement in metabolic acidosis (bicarbonates, p ≤ 0.01; base excess, p ≤ 0.02). Moreover, at T2 the intervention group showed a reduction in serum insulin (p = 0.008) and fasting glucose levels (p = 0.022), HOMA-IR (p = 0.004), as well as lower total serum cholesterol (p = 0.012), triglycerides (p = 0.016), C-reactive protein (p = 0.044) and homocysteine (p = 0.044) and higher HDL (p < 0.001) with respect to baseline. We also observed a significant amelioration of some quality of life and functional status indices (SF-36 survey) among the intervention group compared to controls, without a significant improvement in the cognitive state (MMSE). On the other hand, an amelioration in mood (by HAM-D and BDI-II) was found in the intervention group and in controls (only by BID-II). In conclusion, LPD in association with oral inulin supplementation improved glycemic and lipid metabolism and ameliorated the systemic inflammatory state, likely reducing cardiovascular risk in CKD patients and this may represent a promising therapeutic option, also improving quality of life and mood. Full article
(This article belongs to the Special Issue New Strategies for the Reduction of Uremic Toxins)
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13 pages, 501 KiB  
Article
Vitamin E-Bonded Membranes Do Not Influence Markers of Oxidative Stress in Hemodialysis Patients with Homozygous Glutathione Transferase M1 Gene Deletion
by Petar Djuric, Sonja Suvakov, Tatjana Simic, Dragana Markovic, Djurdja Jerotic, Aleksandar Jankovic, Ana Bulatovic, Jelena Tosic Dragovic, Tatjana Damjanovic, Jelena Marinkovic, Radomir Naumovic and Nada Dimkovic
Toxins 2020, 12(6), 352; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12060352 - 27 May 2020
Cited by 4 | Viewed by 2532
Abstract
Background: Increased oxidative stress is a hallmark of end-stage renal disease. Hemodialysis (HD) patients lacking glutathione transferase M1 (GSTM1) enzyme activity exhibit enhanced oxidative DNA damage and higher mortality rate than those with active GSTM1 enzyme. To our knowledge, this is the first [...] Read more.
Background: Increased oxidative stress is a hallmark of end-stage renal disease. Hemodialysis (HD) patients lacking glutathione transferase M1 (GSTM1) enzyme activity exhibit enhanced oxidative DNA damage and higher mortality rate than those with active GSTM1 enzyme. To our knowledge, this is the first study to use the vitamin E-bonded membranes (VEM) in patients with homozygous GSTM1 gene deletion, and we aimed to determine the effect of VEM on oxidative and inflammatory status in HD patients with homozygous GSTM1 gene deletion. Methods: GSTM1 genotypes were determined by polymerase chain reaction (PCR) in 170 chronic HD patients. Those with GSTM1-null genotype were randomized and 80 were included in the study. Forty of them were dialyzed for three months with VEM, while the other forty were dialyzed with high-flux same-surface polysulfone dialyzers. Markers of protein and lipid oxidative damage and inflammation (thiol groups, malondialdehyde (MDA), Interleukin-6 (IL-6)), together with plasma antioxidant activity (glutathione peroxidase (GPX), superoxide dismutase (SOD)) were determined. Results: Seventy-five patients finished the study. There were no differences at baseline in markers of protein and lipid oxidative damage, inflammation and plasma antioxidant activity. After three months of therapy, GPX, MDA, and thiol groups increased significantly in both groups, but without statistical significance between groups. SOD and C reactive protein (CRP) did not change significantly during the three-month period. IL-6 increased in the control group, and at the same time, decreased in the VEM group, but without statistical significance. Hemoglobin (Hb) value, red blood cells, erythropoiesis resistance index (ERI), serum ferritin and iron did not change significantly within or between groups. Regarding other laboratory parameters, proteins, albumins, triglycerides, serum phosphorus, serum bicarbonate and Kt/V showed significant improvements within groups but with no significant difference between groups. Conclusions: Our data shows that therapy with VEM over three months had no benefit over standard polysulfone membrane in decreasing by-products of oxidative stress and inflammation in dialysis patients lacking GSTM1 enzyme activity. Full article
(This article belongs to the Special Issue New Strategies for the Reduction of Uremic Toxins)
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Review

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14 pages, 2300 KiB  
Review
Removal of Protein-Bound Uremic Toxins Using Binding Competitors in Hemodialysis: A Narrative Review
by Vaibhav Maheshwari, Xia Tao, Stephan Thijssen and Peter Kotanko
Toxins 2021, 13(9), 622; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13090622 - 04 Sep 2021
Cited by 16 | Viewed by 3750
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue New Strategies for the Reduction of Uremic Toxins)
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14 pages, 562 KiB  
Review
Expanded Haemodialysis as a Current Strategy to Remove Uremic Toxins
by Paola Ciceri and Mario Cozzolino
Toxins 2021, 13(6), 380; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13060380 - 26 May 2021
Cited by 15 | Viewed by 3202
Abstract
Chronic kidney disease (CKD) is characterized by the retention of solutes named uremic toxins, which strongly associate with high morbidity and mortality. Mounting evidence suggests that targeting uremic toxins and/or their pathways may decrease the risk of cardiovascular disease in CKD patients. Dialysis [...] Read more.
Chronic kidney disease (CKD) is characterized by the retention of solutes named uremic toxins, which strongly associate with high morbidity and mortality. Mounting evidence suggests that targeting uremic toxins and/or their pathways may decrease the risk of cardiovascular disease in CKD patients. Dialysis therapies have been developed to improve removal of uremic toxins. Advances in our understanding of uremic retention solutes as well as improvements in dialysis membranes and techniques (HDx, Expanded Hemodialysis) will offer the opportunity to ameliorate clinical symptoms and outcomes, facilitate personalized and targeted dialysis treatment, and improve quality of life, morbidity and mortality. Full article
(This article belongs to the Special Issue New Strategies for the Reduction of Uremic Toxins)
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10 pages, 10209 KiB  
Review
Uremic Toxins and Blood Purification: A Review of Current Evidence and Future Perspectives
by Stefania Magnani and Mauro Atti
Toxins 2021, 13(4), 246; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13040246 - 30 Mar 2021
Cited by 27 | Viewed by 3352
Abstract
Accumulation of uremic toxins represents one of the major contributors to the rapid progression of chronic kidney disease (CKD), especially in patients with end-stage renal disease that are undergoing dialysis treatment. In particular, protein-bound uremic toxins (PBUTs) seem to have an important key [...] Read more.
Accumulation of uremic toxins represents one of the major contributors to the rapid progression of chronic kidney disease (CKD), especially in patients with end-stage renal disease that are undergoing dialysis treatment. In particular, protein-bound uremic toxins (PBUTs) seem to have an important key pathophysiologic role in CKD, inducing various cardiovascular complications. The removal of uremic toxins from the blood with dialytic techniques represents a proved approach to limit the CKD-related complications. However, conventional dialysis mainly focuses on the removal of water-soluble compounds of low and middle molecular weight, whereas PBTUs are strongly protein-bound, thus not efficiently eliminated. Therefore, over the years, dialysis techniques have been adapted by improving membranes structures or using combined strategies to maximize PBTUs removal and eventually prevent CKD-related complications. Recent findings showed that adsorption-based extracorporeal techniques, in addition to conventional dialysis treatment, may effectively adsorb a significant amount of PBTUs during the course of the sessions. This review is focused on the analysis of the current state of the art for blood purification strategies in order to highlight their potentialities and limits and identify the most feasible solution to improve toxins removal effectiveness, exploring possible future strategies and applications, such as the study of a synergic approach by reducing PBTUs production and increasing their blood clearance. Full article
(This article belongs to the Special Issue New Strategies for the Reduction of Uremic Toxins)
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16 pages, 1078 KiB  
Review
Medium Cut-Off Dialysis Membrane and Dietary Fiber Effects on Inflammation and Protein-Bound Uremic Toxins: A Systematic Review and Protocol for an Interventional Study
by Tjaša Herič, Tjaša Vivoda, Špela Bogataj and Jernej Pajek
Toxins 2021, 13(4), 244; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13040244 - 29 Mar 2021
Cited by 5 | Viewed by 2419
Abstract
The aim of this systematic review is to investigate the effects of the use of a medium cut-off membrane (MCO) and dietary fiber on the concentration of protein-bound uremic toxins (PBUTs) and inflammatory markers in hemodialysis (HD) patients. Of 11,397 papers originally found, [...] Read more.
The aim of this systematic review is to investigate the effects of the use of a medium cut-off membrane (MCO) and dietary fiber on the concentration of protein-bound uremic toxins (PBUTs) and inflammatory markers in hemodialysis (HD) patients. Of 11,397 papers originally found, eight met the criteria of randomized controlled trial design. No study examined the effects of MCO membranes on PBUTs. Three studies examined the reduction in inflammatory markers with MCO membranes compared to high-flux HD membranes and showed no significant differences. Five studies of dietary fiber supplementation showed an inconclusive positive effect on PBUT levels and a significant positive effect on the reduction in inflammatory markers (interleukin-6 reduction: standardized difference in means −1.18; 95% confidence interval −1.45 to −0.9 for dietary fiber supplementation vs. control; p < 0.001). To date, no study has combined the use of an MCO membrane and fiber supplementation to reduce PBUT levels and inflammation with online hemodiafiltration as a comparator. A rationale and protocol for an interventional trial using a combination of MCO membrane dialysis and fiber supplementation to lower inflammatory markers and PBUT concentrations are presented. Full article
(This article belongs to the Special Issue New Strategies for the Reduction of Uremic Toxins)
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13 pages, 352 KiB  
Review
Intestinal Chelators, Sorbants, and Gut-Derived Uremic Toxins
by Solène M. Laville, Ziad A. Massy, Said Kamel, Jean Marc Chillon, Gabriel Choukroun and Sophie Liabeuf
Toxins 2021, 13(2), 91; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13020091 - 26 Jan 2021
Cited by 11 | Viewed by 3003
Abstract
Chronic kidney disease (CKD) is a highly prevalent condition and is associated with a high comorbidity burden, polymedication, and a high mortality rate. A number of conventional and nonconventional risk factors for comorbidities and mortality in CKD have been identified. Among the nonconventional [...] Read more.
Chronic kidney disease (CKD) is a highly prevalent condition and is associated with a high comorbidity burden, polymedication, and a high mortality rate. A number of conventional and nonconventional risk factors for comorbidities and mortality in CKD have been identified. Among the nonconventional risk factors, uremic toxins are valuable therapeutic targets. The fact that some uremic toxins are gut-derived suggests that intestinal chelators might have a therapeutic effect. The phosphate binders used to prevent hyperphosphatemia in hemodialysis patients act by complexing inorganic phosphate in the gastrointestinal tract but might conceivably have a nonspecific action on gut-derived uremic toxins. Since phosphorous is a major nutrient for the survival and reproduction of bacteria, changes in its intestinal concentration may impact the gut microbiota’s activity and composition. Furthermore, AST-120 is an orally administered activated charcoal adsorbent that is widely used in Asian countries to specifically decrease uremic toxin levels. In this narrative review, we examine the latest data on the use of oral nonspecific and specific intestinal chelators to reduce levels of gut-derived uremic toxins. Full article
(This article belongs to the Special Issue New Strategies for the Reduction of Uremic Toxins)
15 pages, 323 KiB  
Review
Targeting Uremic Toxins to Prevent Peripheral Vascular Complications in Chronic Kidney Disease
by Chia-Lin Wu and Der-Cherng Tarng
Toxins 2020, 12(12), 808; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12120808 - 20 Dec 2020
Cited by 5 | Viewed by 2489
Abstract
Chronic kidney disease (CKD) exhibits progressive kidney dysfunction and leads to disturbed homeostasis, including accumulation of uremic toxins, activated renin-angiotensin system, and increased oxidative stress and proinflammatory cytokines. Patients with CKD are prone to developing the peripheral vascular disease (PVD), leading to poorer [...] Read more.
Chronic kidney disease (CKD) exhibits progressive kidney dysfunction and leads to disturbed homeostasis, including accumulation of uremic toxins, activated renin-angiotensin system, and increased oxidative stress and proinflammatory cytokines. Patients with CKD are prone to developing the peripheral vascular disease (PVD), leading to poorer outcomes than those without CKD. Cumulative evidence has showed that the synergy of uremic milieu and PVD could exaggerate vascular complications such as limb ischemia, amputation, stenosis, or thrombosis of a dialysis vascular access, and increase mortality risk. The role of uremic toxins in the pathogenesis of vascular dysfunction in CKD has been investigated. Moreover, growing evidence has shown the promising role of uremic toxins as a therapeutic target for PVD in CKD. This review focused on uremic toxins in the pathophysiology, in vitro and animal models, and current novel clinical approaches in reducing the uremic toxin to prevent peripheral vascular complications in CKD patients. Full article
(This article belongs to the Special Issue New Strategies for the Reduction of Uremic Toxins)

Other

13 pages, 534 KiB  
Concept Paper
Protection of Residual Renal Function and Nutritional Treatment: First Step Strategy for Reduction of Uremic Toxins in End-Stage Kidney Disease Patients
by Adamasco Cupisti, Piergiorgio Bolasco, Claudia D’Alessandro, Domenico Giannese, Alice Sabatino and Enrico Fiaccadori
Toxins 2021, 13(4), 289; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13040289 - 19 Apr 2021
Cited by 14 | Viewed by 3714
Abstract
The retention of uremic toxins and their pathological effects occurs in the advanced phases of chronic kidney disease (CKD), mainly in stage 5, when the implementation of conventional thrice-weekly hemodialysis is the prevalent and life-saving treatment. However, the start of hemodialysis is associated [...] Read more.
The retention of uremic toxins and their pathological effects occurs in the advanced phases of chronic kidney disease (CKD), mainly in stage 5, when the implementation of conventional thrice-weekly hemodialysis is the prevalent and life-saving treatment. However, the start of hemodialysis is associated with both an acceleration of the loss of residual kidney function (RKF) and the shift to an increased intake of proteins, which are precursors of uremic toxins. In this phase, hemodialysis treatment is the only way to remove toxins from the body, but it can be largely inefficient in the case of high molecular weight and/or protein-bound molecules. Instead, even very low levels of RKF are crucial for uremic toxins excretion, which in most cases are protein-derived waste products generated by the intestinal microbiota. Protection of RKF can be obtained even in patients with end-stage kidney disease (ESKD) by a gradual and soft shift to kidney replacement therapy (KRT), for example by combining a once-a-week hemodialysis program with a low or very low-protein diet on the extra-dialysis days. This approach could represent a tailored strategy aimed at limiting the retention of both inorganic and organic toxins. In this paper, we discuss the combination of upstream (i.e., reduced production) and downstream (i.e., increased removal) strategies to reduce the concentration of uremic toxins in patients with ESKD during the transition phase from pure conservative management to full hemodialysis treatment. Full article
(This article belongs to the Special Issue New Strategies for the Reduction of Uremic Toxins)
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