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Toxins
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New Insights in Uremic Toxins and Toxin-Related Outcomes in Chronic...
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New Insights in Uremic Toxins and Toxin-Related Outcomes in Chronic Kidney Disease

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

Deadline for manuscript submissions: 31 August 2026 | Viewed by 9309

Special Issue Editors

Prof. Dr. Griet Glorieux

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Guest Editor
Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent University, 9000 Gent, Belgium
Interests: uremic toxins; protein-bound uremic toxins; chronic kidney disease; leukocyte/monocyte function; leukocyte–endothelial interaction; inflammation in CKD; dialysis fluid purity/endotoxins; gut–kidney axis
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Evelien Snauwaert

E-Mail Website
Guest Editor
Department of Internal Medicine and Pediatrics, Ghent University Hospital, 9000 Ghent, Belgium
Interests: uraemic toxins; chronic kidney disease; pediatrics; Hemodialysis
Prof. Dr. Raymond Vanholder

grade E-Mail Website1 Website2
Guest Editor
Nephrology Section, 0K12, Department of Internal Medicine, Ghent University Hospital, 9000 Ghent, Belgium
Interests: uremia; chronic kidney disease; hemodialysis; adequacy of dialysis; acute kidney injury
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Over the past decade, insights into uremic toxicity have evolved. The introduction of metabolome analyses has offered a more balanced view on uremic retention by revealing the accumulation of not only toxic but also potentially beneficial retention metabolites. All these metabolites, which are secreted by organs or absorbed via the intestine into the circulation, can, together with signaling molecules, receptors, transporter proteins and enzymes, remotely affect multiple organs and lead to disordered communication. Knowledge about the origin (diet, gut microbiota and host metabolism) and biological impact (increased inflammation and sex-related aspects) of uremic toxins has grown. A lot can also be learned from veterinary studies on uremic toxins in kidney disease. While promising innovations for the treatment of advanced kidney failure, such as portable dialysis and bio-artificial kidneys, are under development, increased attention is now also paid to preventive and life-style measures to limit the accumulation of uremic toxins, their toxicity, and their effect on outcomes in CKD. This Special Issue, titled “New Insights in Uremic Toxins and Toxin-Related Outcomes in Chronic Kidney Disease”, welcomes submissions related to the topics described above.

Prof. Dr. Griet Glorieux
Prof. Dr. Evelien Snauwaert
Prof. Dr. Raymond Vanholder
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 250 words) can be sent to the Editorial Office for assessment.

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 toxins
  • metabolome
  • nutrition
  • diet
  • dialysis
  • sex-related
  • inflammation
  • aryl hydrocarbon receptor
  • post-translational modifications
  • human
  • veterinary

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Published Papers (7 papers)

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Research

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16 pages, 1801 KB  
Article
Kidney Function Modulates Gut Microbial Metabolism
by Mara Lauriola, Sophie Valkenburg, Sander Dejongh, Ward Zadora, Hubert Krukowski, Pieter Evenepoel, Jeroen Raes, Ricard Farré, Griet Glorieux and Björn Meijers
Toxins 2026, 18(4), 176; https://doi.org/10.3390/toxins18040176 - 4 Apr 2026
Viewed by 412
Abstract
Growing evidence suggests that chronic kidney disease (CKD) profoundly disrupts gut microbiome and its activity. This study explores how CKD affects colon microbial metabolism, focusing on (1) the representativeness of fecal metabolomics, (2) saccharolytic and proteolytic fermentation metabolites, and (3) the gut microbiome’s [...] Read more.
Growing evidence suggests that chronic kidney disease (CKD) profoundly disrupts gut microbiome and its activity. This study explores how CKD affects colon microbial metabolism, focusing on (1) the representativeness of fecal metabolomics, (2) saccharolytic and proteolytic fermentation metabolites, and (3) the gut microbiome’s role in the partitioning of tryptophan in its metabolic pathways. Tryptophan’s main metabolic pathways include the indolic and the kynurenine pathways, which lead, respectively, to the formation of indoxyl sulfate and kynurenine, both contributing to uremic toxicity. Using a rat model of CKD, we evaluated whether fecal concentrations of microbial compounds, on which most studies are based, reflect the colonic concentrations in contact with the gut mucosa. Thus, we quantified the concentration and content of amino acids, indole, p-cresol, and also short-chain fatty acids, in different colon sections. We demonstrated that CKD promotes increased proteolytic fermentation and an augmented tryptophan partitioning into both the indolic and kynurenine pathways. Depletion of the indolic pathway obtained upon antibiotic treatment leads to a further enhancement of the kynurenine pathway. Full article
(This article belongs to the Special Issue New Insights in Uremic Toxins and Toxin-Related Outcomes in Chronic Kidney Disease)
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11 pages, 610 KB  
Article
Elevated Indoxyl Sulfate Levels Correlate with Increased Aortic Stiffness in Patients Undergoing Kidney Transplantation
by Hsiao-Hui Yang, Chin-Hung Liu, Yen-Cheng Chen and Bang-Gee Hsu
Toxins 2026, 18(2), 71; https://doi.org/10.3390/toxins18020071 - 30 Jan 2026
Viewed by 615
Abstract
Although kidney transplantation (KT) restores renal function, residual uremic toxins, such as indoxyl sulfate (IS), may persist and contribute to vascular remodeling and aging. Aortic stiffness, reflected by carotid–femoral pulse wave velocity (cfPWV), is a strong predictor of cardiovascular events. This study enrolled [...] Read more.
Although kidney transplantation (KT) restores renal function, residual uremic toxins, such as indoxyl sulfate (IS), may persist and contribute to vascular remodeling and aging. Aortic stiffness, reflected by carotid–femoral pulse wave velocity (cfPWV), is a strong predictor of cardiovascular events. This study enrolled KT recipients to examine the association of circulating IS with aortic stiffness. Using the SphygmoCor system, we assessed aortic stiffness, which was defined as cfPWV > 10 m/s. Serum IS concentrations were measured by liquid chromatography–tandem mass spectrometry. Of 94 KT recipients, 26 (27.7%) met the criteria for aortic stiffness. Compared with patients without aortic stiffness, those with aortic stiffness were older (p = 0.017) and had significantly higher systolic blood pressure (p = 0.011) and fasting glucose levels (p = 0.002), a higher prevalence of diabetes (p = 0.043), and higher IS levels (p = 0.002). According to multivariable logistic regression, serum IS remained independently associated with aortic stiffness (p = 0.017). According to stepwise linear regression, log-transformed IS further showed a positive correlation with cfPWV (p = 0.016). Serum IS remained an independent determinant of aortic stiffness in KT recipients, highlighting the burden of residual uremic toxins as a contributor to post-transplant vascular aging. Full article
(This article belongs to the Special Issue New Insights in Uremic Toxins and Toxin-Related Outcomes in Chronic Kidney Disease)
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11 pages, 4520 KB  
Article
Kynurenine Promotes Phosphate-Induced Endothelial Calcification via Endothelial-to-Mesenchymal Transition, Osteoblastic Differentiation and AhR Activation
by Martina Molinaro, Mario Cozzolino and Paola Ciceri
Toxins 2025, 17(8), 421; https://doi.org/10.3390/toxins17080421 - 19 Aug 2025
Cited by 1 | Viewed by 1409
Abstract
In end-stage renal disease (ESRD), the accumulation of solutes normally excreted by the kidneys contributes to multiple complications, including vascular calcification (VC), a key factor in the heightened cardiovascular risk seen in these patients. Among VC drivers, hyperphosphatemia and the uremic milieu are [...] Read more.
In end-stage renal disease (ESRD), the accumulation of solutes normally excreted by the kidneys contributes to multiple complications, including vascular calcification (VC), a key factor in the heightened cardiovascular risk seen in these patients. Among VC drivers, hyperphosphatemia and the uremic milieu are major contributors. Kynurenine, a tryptophan metabolite classified as a uremic toxin, may further exacerbate this process. This study investigated whether kynurenine amplifies high phosphate (Pi)-induced calcification in human aortic endothelial cells (HAEC). Cells were treated with Pi and kynurenine for up to seven days. Kynurenine increased Pi-induced calcium deposition by 36%, accompanied by enhanced endothelial-to-mesenchymal transition (EndMT) and osteoblastic differentiation. Mechanistically, kynurenine activated the aryl hydrocarbon receptor (AhR) pathway, and pharmacological inhibition of AhR partially attenuated this effect. These findings suggest that kynurenine contributes to VC in ESRD by potentiating phosphate-induced endothelial dysfunction via AhR signaling. Full article
(This article belongs to the Special Issue New Insights in Uremic Toxins and Toxin-Related Outcomes in Chronic Kidney Disease)
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Review

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21 pages, 1130 KB  
Review
Indoxyl Sulfate in the Gut–Kidney Axis: Pathophysiology and Clinical Significance in CKD-Associated Colorectal Cancer
by Hidehisa Shimizu and Toshimitsu Niwa
Toxins 2026, 18(2), 72; https://doi.org/10.3390/toxins18020072 - 30 Jan 2026
Viewed by 1150
Abstract
Chronic Kidney Disease (CKD) and Colorectal Cancer (CRC) share a profound epidemiological link, supported by Mendelian randomization studies suggesting causality. This review articulates a refined Gut–Kidney Axis, focusing on the pathophysiology of indole-derived uremic toxins. CKD-induced dysbiosis drives hepatic synthesis and systemic accumulation [...] Read more.
Chronic Kidney Disease (CKD) and Colorectal Cancer (CRC) share a profound epidemiological link, supported by Mendelian randomization studies suggesting causality. This review articulates a refined Gut–Kidney Axis, focusing on the pathophysiology of indole-derived uremic toxins. CKD-induced dysbiosis drives hepatic synthesis and systemic accumulation of indoxyl sulfate, which is proposed to promote carcinogenesis via Aryl Hydrocarbon Receptor (AhR) and Akt signaling, ultimately upregulating c-Myc and EGFR. We propose a two-compartment model: while systemic indoxyl sulfate reflects the total gut indole pool (mainly from planktonic bacteria), adherent bacteria like Fusobacterium nucleatum may create high-concentration indole hotspots within the tumor microenvironment. Clinically, we advocate for protein-independent DNA methylation biomarkers (SEPT9, SDC2) to avoid renal confounding. Furthermore, we propose a novel diagnostic panel integrating serum indoxyl sulfate (systemic load) and urinary indoxyl sulfate (gut production) to guide therapy. Therapeutically, targeting upstream drivers (AhR/Akt) may bypass resistance to anti-EGFR therapies in KRAS-mutated tumors. We also discuss the repurposing of the oral adsorbent AST-120 and emerging bacteriophage therapies as strategies to disrupt this oncogenic axis. This review offers a comprehensive framework for stratified management of CKD-associated CRC. Full article
(This article belongs to the Special Issue New Insights in Uremic Toxins and Toxin-Related Outcomes in Chronic Kidney Disease)
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22 pages, 1604 KB  
Review
Strategies for Removal of Protein-Bound Uremic Toxins in Hemodialysis
by Joost C. de Vries, João G. Brás, Geert M. de Vries, Jeroen C. Vollenbroek, Fokko P. Wieringa, Joachim Jankowski, Marianne C. Verhaar, Dimitrios Stamatialis, Rosalinde Masereeuw and Karin G. F. Gerritsen
Toxins 2026, 18(1), 57; https://doi.org/10.3390/toxins18010057 - 22 Jan 2026
Cited by 1 | Viewed by 1562
Abstract
The removal of protein-bound uremic toxins (PBUTs) from the blood of kidney failure patients with conventional dialysis is limited. However, as their harmful effects and association with morbidity and mortality in dialysis patients are increasingly recognized, PBUTs have become important therapeutic targets. In [...] Read more.
The removal of protein-bound uremic toxins (PBUTs) from the blood of kidney failure patients with conventional dialysis is limited. However, as their harmful effects and association with morbidity and mortality in dialysis patients are increasingly recognized, PBUTs have become important therapeutic targets. In this review, PBUT removal with current state-of-the-art dialysis technologies and future perspectives are discussed. Strategies to enhance PBUT clearance include methods that interfere with PBUT–albumin binding, such as chemical displacers, high ionic strength, pH changes, or electromagnetic fields, thereby increasing the free fraction available for dialysis. While these methods have shown promise in vitro, and some also in vivo, long-term safety data are lacking. PBUT removal can also be increased by adsorption, either directly via hemoperfusion, or indirectly, e.g., via sorbents incorporated in a mixed-matrix membrane or dissolved in the dialysate. In the kidney, PBUTs are secreted in the proximal tubules; hence, a cell-based bioartificial kidney (BAK) that secretes PBUTs is proposed as an add-on to current dialysis. Yet both PBUT adsorption strategies and, in particular, BAKs face considerable challenges in upscaling and mass production at acceptable costs. In conclusion, many novel technologies are under development, all requiring further (pre)clinical testing and upscaling before these strategies can be applied in the clinic. Full article
(This article belongs to the Special Issue New Insights in Uremic Toxins and Toxin-Related Outcomes in Chronic Kidney Disease)
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21 pages, 1902 KB  
Review
Targeting the Gut–Kidney Axis: Modulation of Gut Microbiota by Traditional Chinese Medicine for Chronic Kidney Disease Management
by Yijing Xin and Libin Pan
Toxins 2025, 17(12), 599; https://doi.org/10.3390/toxins17120599 - 15 Dec 2025
Viewed by 2252
Abstract
The interaction between gut microbiota dysbiosis and CKD progression via the “gut–kidney axis” is increasingly recognized. Gut-derived uremic toxins (e.g., indoxyl sulfate and p-cresyl sulfate) accumulate systemically, while beneficial metabolites like short-chain fatty acids (SCFAs) decrease, contributing to inflammation, oxidative stress, and kidney [...] Read more.
The interaction between gut microbiota dysbiosis and CKD progression via the “gut–kidney axis” is increasingly recognized. Gut-derived uremic toxins (e.g., indoxyl sulfate and p-cresyl sulfate) accumulate systemically, while beneficial metabolites like short-chain fatty acids (SCFAs) decrease, contributing to inflammation, oxidative stress, and kidney fibrosis. Traditional Chinese Medicine (TCM), including complex formulae, single herbs, and active ingredients, has long been used to manage CKD. Emerging evidence—primarily from animal studies—highlights its potential to alleviate the disease by modulating the gut microbiota. This review summarizes how TCM interventions re-establish gut microbial symbiosis by regulating microbial composition, reducing toxin load, and reinforcing intestinal barrier integrity, thereby ameliorating systemic inflammation and protecting kidney function. Targeting the gut microbiota represents a promising therapeutic frontier for CKD, and TCM offers a rich resource for developing novel microbiota-modulating strategies. However, future research must focus on validating molecular mechanisms, standardizing TCM preparations, and conducting rigorous clinical trials to facilitate clinical translation. Full article
(This article belongs to the Special Issue New Insights in Uremic Toxins and Toxin-Related Outcomes in Chronic Kidney Disease)
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Other

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9 pages, 1002 KB  
Brief Report
Effect of Expanded Hemodialysis with the Theranova Dialyzer on the Platelet-to-Lymphocyte Ratio and Inflammatory Markers
by You Hyun Jeon, Hee-Yeon Jung, Ji-Young Choi, Sun-Hee Park, Chan-Duck Kim, Yong-Lim Kim, Jeong-Hoon Lim and Jang-Hee Cho
Toxins 2025, 17(11), 521; https://doi.org/10.3390/toxins17110521 - 22 Oct 2025
Viewed by 1288
Abstract
The platelet-to-lymphocyte ratio (PLR) has been used as a marker of inflammation, endothelial damage, and a predictor of mortality. Expanded hemodialysis (HDx) using medium cut-off dialyzer (MCO) can effectively clear medium-sized uremic toxins. This study evaluated the effect of the Theranova dialyzer, a [...] Read more.
The platelet-to-lymphocyte ratio (PLR) has been used as a marker of inflammation, endothelial damage, and a predictor of mortality. Expanded hemodialysis (HDx) using medium cut-off dialyzer (MCO) can effectively clear medium-sized uremic toxins. This study evaluated the effect of the Theranova dialyzer, a type of MCO dialyzer, on PLR and uremia-related inflammatory markers. A total of 44 patients with maintenance hemodialysis (HD) using high-flux dialyzer were randomly allocated to the Theranova or high-flux group. PLR and inflammatory markers including fibroblast growth factor 23, tumor necrosis factor-α (TNF-α), and interleukin 6 were evaluated every 4 weeks. The changes in PLR and the reduction ratio of inflammatory markers were compared between two groups during the 12-week study period. The baseline characteristics and PLR were not different between groups. After 12 weeks, the levels of PLR, and TNF-α were significantly lower in the Theranova group compared to the high-flux group (all p < 0.05). The generalized estimating equation model also revealed a significant decrease in PLR over time in the Theranova group than in the high-flux group (p = 0.04). The fold change in 12-week PLR to baseline PLR was lower in the Theranova group than in the high-flux group (p = 0.03). In the multivariable linear regression analysis, the Theranova dialyzer showed a negative correlation with the PLR fold change (β = −0.32, p = 0.04). Our results showed that HDx using the Theranova dialyzer improves PLR over time compared to the high-flux HD. The superior removal of the inflammatory uremic toxins by the Theranova dialyzer may have reduced inflammation and inflammation-related complications in HD patients. Full article
(This article belongs to the Special Issue New Insights in Uremic Toxins and Toxin-Related Outcomes in Chronic Kidney Disease)
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