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The Two-Fold Role of Uremic Retention Molecules as Toxins and Signaling Molecules

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

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 15040

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Special Issue Editors

Prof. Dr. Jerome Lowenstein

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Guest Editor

Renal Division, Department of Medicine, New York University Medical Center, 550 First Avenue, New York, NY 10016, USA
Interests: chronic renal failure; uremic toxin

Prof. Dr. Björn Meijers

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Guest Editor

1. Laboratory of Nephrology, Department of Immunology and Microbiology, KU Leuven—University of Leuven, B-3000 Leuven, Belgium;
2. Department of Nephrology and Renal Transplantation, University Hospitals Leuven, B-3000 Leuven, Belgium
Interests: uremic toxicity; protein-bound toxins; chronic kidney disease; hemodialysis; blood purification; P-cresol sulphate; indoxyl sulphate

Special Issue Information

Dear Colleagues,

While nephrologists have been conditioned to think in terms of uremic “toxins”, this traditional view is challenged by a number of observations. First, most uremic toxins and uremic solutes are present in the body in the absence of kidney dysfunction. In addition to OATs, there are transporters of these small molecules in many non-renal tissues. One possibility, consistent with a growing amount of biochemical and molecular data, is that so-called uremic toxins, while harmful when in excess in the setting of kidney failure, might have other important “non-toxic” roles in normal biology, including metabolism, signaling, regulating redox state, and gut microbiome population dynamics.

Prof. Dr. Jerome Lowenstein
Prof. Dr. Björn Meijers
Guest Editors

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.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

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 retention solutes
organic anion transporters
sensing and signaling
aryl hydrocarbon receptor
EGF receptor

Published Papers (5 papers)

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Review

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9 pages, 1594 KiB

Open AccessReview

The Evolving View of Uremic Toxicity

by Bjorn Meijers and Jerome Lowenstein

Toxins 2022, 14(4), 274; https://doi.org/10.3390/toxins14040274 - 12 Apr 2022

Cited by 2 | Viewed by 2177

Abstract

Indoxyl sulfate, closely related to indigo, a dye valued for it binding to cloth, has been recognized as a protein-bound solute bound to albumin, present in increased concentration in the serum of patients with impaired glomerular filtration (13). The early studies of Niwa identified indoxyl sulfate as a toxin capable of accelerating the rate of renal damage in subtotal nephrectomized rats (18). Over the past decade other protein-bound solutes have been identified in the plasma of patients with impaired glomerular filtration. Although the early studies, focused on the kidney, identified indoxyl sulfate as a toxic waste product dependent on the kidney for its removal, subsequent observations have identified organic anion transporters on many non-renal tissue, leading to the view that indoxyl sulfate is part of a systemic signaling system. Full article

(This article belongs to the Special Issue The Two-Fold Role of Uremic Retention Molecules as Toxins and Signaling Molecules)

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17 pages, 803 KiB

Open AccessReview

The Microbiome and Uremic Solutes

by Nadim Zaidan and Lama Nazzal

Toxins 2022, 14(4), 245; https://doi.org/10.3390/toxins14040245 - 30 Mar 2022

Cited by 4 | Viewed by 2825

Abstract

Uremic retention solutes, especially the protein-bound compounds, are toxic metabolites, difficult to eliminate with progressive renal functional decline. They are of particular interest because these uremic solutes are responsible for the pathogenesis of cardiovascular and chronic kidney diseases. Evidence suggests that the relation between uremic toxins, the microbiome, and its host is altered in patients with chronic kidney disease, with the colon’s motility, epithelial integrity, and absorptive properties also playing an important role. Studies found an alteration of the microbiota composition with differences in species proportion, diversity, and function. Since uremic toxins precursors are generated by the microbiota, multiple therapeutic options are currently being explored to address dysbiosis. While an oral adsorbent can decrease the transport of bacterial metabolites from the intestinal lumen to the blood, dietary measures, supplements (prebiotics, probiotics, and synbiotics), and antibiotics aim to target directly the gut microbiota composition. Innovative approaches, such as the modulation of bacterial enzymes, open new perspectives to decrease the plasma level of uremic toxins. Full article

(This article belongs to the Special Issue The Two-Fold Role of Uremic Retention Molecules as Toxins and Signaling Molecules)

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25 pages, 7724 KiB

Open AccessReview

What If Not All Metabolites from the Uremic Toxin Generating Pathways Are Toxic? A Hypothesis

by Raymond Vanholder, Sanjay K. Nigam, Stéphane Burtey and Griet Glorieux

Toxins 2022, 14(3), 221; https://doi.org/10.3390/toxins14030221 - 17 Mar 2022

Cited by 18 | Viewed by 4690

Abstract

The topic of uremic toxicity has received broad attention from the nephrological community over the past few decades. An aspect that is much less often considered is the possibility that the metabolic pathways that generate uremic toxins also may produce molecules that benefit body functions. Here, we discuss this dualism based on the example of tryptophan-derived metabolites, which comprise elements that are mainly toxic, such as indoxyl sulfate, kynurenine and kynurenic acid, but also beneficial compounds, such as indole, melatonin and indole-3-propionic acid, and ambivalent (beneficial for some aspects and harmful for others) compounds such as serotonin. This dualism can also be perceived at the level of the main receptor of the tryptophan-derived metabolites, the aryl hydrocarbon receptor (AHR), which has also been linked to both harm and benefit. We hypothesize that these beneficial effects are the reason why uremic toxin generation remained preserved throughout evolution. This duality is also not unique for the tryptophan-derived metabolites, and in this broader context we discuss the remote sensing and signaling theory (RSST). The RSST proposes that transporters (e.g., organic anion transporter 1—OAT1; ATP-binding cassette transporter G—ABCG2) and drug metabolizing enzymes form a large network of proteins interacting to promote small molecule remote communication at the inter-organ (e.g., gut–liver–heart–brain–kidney) and inter-organismal (e.g., gut microbe–host) levels. These small molecules include gut microbe-derived uremic toxins as well as beneficial molecules such as those discussed here. We emphasize that this positive side of uremic metabolite production needs more attention, and that this dualism especially needs to be considered when assessing and conceiving of therapeutic interventions. These homeostatic considerations are central to the RSST and suggest that interventions be aimed at preserving or restoring the balance between positive and negative components rather than eliminating them all without distinction. Full article

(This article belongs to the Special Issue The Two-Fold Role of Uremic Retention Molecules as Toxins and Signaling Molecules)

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8 pages, 6732 KiB

Open AccessEditor’s ChoiceReview

Effects of an SGLT Inhibitor on the Production, Toxicity, and Elimination of Gut-Derived Uremic Toxins: A Call for Additional Evidence

by Pieter Evenepoel, Bjorn Meijers, Rosalinde Masereeuw and Jerome Lowenstein

Toxins 2022, 14(3), 210; https://doi.org/10.3390/toxins14030210 - 15 Mar 2022

Cited by 6 | Viewed by 2809

Abstract

Sodium–glucose cotransporter (SGLT) inhibitors are a class of oral hypoglycemic agents, which, in recent years, have been shown to improve renal and cardiovascular outcomes in patients with diabetic and non-diabetic chronic kidney disease. There remains considerable debate regarding the potential glucose-independent mechanisms by which these benefits are conferred. SGLT inhibitors, to a variable extent, impair small intestinal glucose absorption, facilitating the delivery of glucose into the colon. This suppresses protein fermentation, and thus the generation of uremic toxins such as phenols and indoles. It is acknowledged that such a shift in gut microbial metabolism yields health benefits for the host. SGLT inhibition, in addition, may be hypothesized to foster the renal clearance of protein-bound uremic toxins. Altered generation and elimination of uremic toxins may be in the causal pathway between SGLT inhibition and improved cardiometabolic health. Present review calls for additional research. Full article

(This article belongs to the Special Issue The Two-Fold Role of Uremic Retention Molecules as Toxins and Signaling Molecules)

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8 pages, 1117 KiB

Open AccessOpinion

The Dual Roles of Protein-Bound Solutes as Toxins and Signaling Molecules in Uremia

by Rosalinde Masereeuw

Toxins 2022, 14(6), 402; https://doi.org/10.3390/toxins14060402 - 11 Jun 2022

Cited by 3 | Viewed by 1803

Abstract

In patients with severe kidney disease, renal clearance is compromised, resulting in the accumulation of a plethora of endogenous waste molecules that cannot be removed by current dialysis techniques, the most often applied treatment. These uremic retention solutes, also named uremic toxins, are a heterogeneous group of organic compounds of which many are too large to be filtered and/or are protein-bound. Their renal excretion depends largely on renal tubular secretion, by which the binding is shifted towards the free fraction that can be eliminated. To facilitate this process, kidney proximal tubule cells are equipped with a range of transport proteins that cooperate in cellular uptake and urinary excretion. In recent years, innovations in dialysis techniques to advance uremic toxin removal, as well as treatments with drugs and/or dietary supplements that limit uremic toxin production, have provided some clinical improvements or are still in progress. This review gives an overview of these developments. Furthermore, the role protein-bound uremic toxins play in inter-organ communication, in particular between the gut (the side where toxins are produced) and the kidney (the side of their removal), is discussed. Full article

(This article belongs to the Special Issue The Two-Fold Role of Uremic Retention Molecules as Toxins and Signaling Molecules)

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