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Toxins
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Disposition of Uremic Toxins: The Challenges in Uremia
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Disposition of Uremic Toxins: The Challenges in Uremia

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

Deadline for manuscript submissions: closed (31 March 2019) | Viewed by 33886

Special Issue Editor

Prof. Dr. Rosalinde Masereeuw

E-Mail Website
Guest Editor
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands
Interests: Kidney failure, pharmaco- and toxicokinetics, renal tubular transport, drug metabolism, clearance, drug induced toxicity

Special Issue Information

Dear Colleagues,

In patients with chronic kidney disease, adequate renal clearance is compromised, resulting in the accumulation of a plethora of uremic solutes. These uremic retention solutes, also named uremic toxins, are a heterogeneous group of organic compounds with intrinsic biological activities. Replacement therapies, such as hemodialysis, only partially restores kidney function as they remove mainly small, unbound substances from the circulation, while leaving large, compartmentalized and protein-bound uremic retention solutes untouched. A better understanding of the aspects associated with the disposition of protein-bound uremic toxins, will aid in developing better therapies for kidney disease patients. This Special Issue of Toxins will include original research articles and mini-reviews on the role of intestinal and hepatic metabolism of uremic solutes, their binding to plasma proteins and disposition-associated transport mechanisms, as well as excretion pathways for the toxins.

Prof. Dr. Rosalinde Masereeuw
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.

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

  • kidney disease
  • uremic toxins
  • protein binding
  • hepatic uptake
  • renal excretion
  • transport proteins

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Published Papers (7 papers)

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Research

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15 pages, 1245 KiB  
Article
Selective Transport of Protein-Bound Uremic Toxins in Erythrocytes
by Olivier Deltombe, Griet Glorieux, Sami Marzouki, Rosalinde Masereeuw, Daniel Schneditz and Sunny Eloot
Toxins 2019, 11(7), 385; https://doi.org/10.3390/toxins11070385 - 1 Jul 2019
Cited by 11 | Viewed by 3224
Abstract
To better understand the kinetics of protein-bound uremic toxins (PBUTs) during hemodialysis (HD), we investigated the distribution of hippuric acid (HA), indole-3-acetic acid (IAA), indoxyl sulfate (IS), and p-cresyl sulfate (pCS) in erythrocytes of HD patients. Their transport across the [...] Read more.
To better understand the kinetics of protein-bound uremic toxins (PBUTs) during hemodialysis (HD), we investigated the distribution of hippuric acid (HA), indole-3-acetic acid (IAA), indoxyl sulfate (IS), and p-cresyl sulfate (pCS) in erythrocytes of HD patients. Their transport across the erythrocyte membrane was explored in the absence of plasma proteins in vitro in a series of loading and unloading experiments of erythrocytes from healthy subjects and HD patients, respectively. Furthermore, the impact of three inhibitors of active transport proteins in erythrocytes was studied. The four PBUTs accumulated in erythrocytes from HD patients. From loading and unloading experiments, it was found that (i) the rate of transport was dependent on the studied PBUT and increased in the following sequence: HA < IS < pCS < IAA and (ii) the solute partition of intra- to extra-cellular concentrations was uneven at equilibrium. Finally, inhibiting especially Band 3 proteins affected the transport of HA (both in loading and unloading), and of IS and pCS (loading). By exploring erythrocyte transmembrane transport of PBUTs, their kinetics can be better understood, and new strategies to improve their dialytic removal can be developed. Full article
(This article belongs to the Special Issue Disposition of Uremic Toxins: The Challenges in Uremia)
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17 pages, 627 KiB  
Article
Connective Tissue Growth Factor Is Related to All-cause Mortality in Hemodialysis Patients and Is Lowered by On-line Hemodiafiltration: Results from the Convective Transport Study
by Claire H. den Hoedt, Maaike K. van Gelder, Muriel P. Grooteman, Menso J. Nubé, Peter J. Blankestijn, Roel Goldschmeding, Robbert Jan Kok, Michiel L. Bots, Marinus A. van den Dorpel and Karin G. F. Gerritsen
Toxins 2019, 11(5), 268; https://doi.org/10.3390/toxins11050268 - 13 May 2019
Cited by 4 | Viewed by 3026
Abstract
Connective tissue growth factor (CTGF) plays a key role in the pathogenesis of tissue fibrosis. The aminoterminal fragment of CTGF is a middle molecule that accumulates in chronic kidney disease. The aims of this study are to explore determinants of plasma CTGF in [...] Read more.
Connective tissue growth factor (CTGF) plays a key role in the pathogenesis of tissue fibrosis. The aminoterminal fragment of CTGF is a middle molecule that accumulates in chronic kidney disease. The aims of this study are to explore determinants of plasma CTGF in hemodialysis (HD) patients, investigate whether CTGF relates to all-cause mortality in HD patients, and investigate whether online-hemodiafiltration (HDF) lowers CTGF. Data from 404 patients participating in the CONvective TRAnsport STudy (CONTRAST) were analyzed. Patients were randomized to low-flux HD or HDF. Pre-dialysis CTGF was measured by sandwich ELISA at baseline, after six and 12 months. CTGF was inversely related in multivariable analysis to glomerular filtration rate (GFR) (p < 0.001) and positively to cardiovascular disease (CVD) (p = 0.006), dialysis vintage (p < 0.001), interleukin-6 (p < 0.001), beta-2-microglobulin (p = 0.045), polycystic kidney disease (p < 0.001), tubulointerstitial nephritis (p = 0.002), and renal vascular disease (p = 0.041). Patients in the highest quartile had a higher mortality risk compared to those in the lowest quartile (HR 1.7, 95% CI: 1.02–2.88, p = 0.043). HDF lowered CTGF with 4.8% between baseline and six months, whereas during HD, CTGF increased with 4.9% (p < 0.001). In conclusion, in HD patients, CTGF is related to GFR, CVD and underlying renal disease and increased the risk of all-cause mortality. HDF reduces CTGF. Full article
(This article belongs to the Special Issue Disposition of Uremic Toxins: The Challenges in Uremia)
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15 pages, 828 KiB  
Article
Uremic Toxin Concentrations are Related to Residual Kidney Function in the Pediatric Hemodialysis Population
by Evelien Snauwaert, Els Holvoet, Wim Van Biesen, Ann Raes, Griet Glorieux, Johan Vande Walle, Sanne Roels, Raymond Vanholder, Varvara Askiti, Karolis Azukaitis, Aysun Bayazit, Nur Canpolat, Michel Fischbach, Nathalie Godefroid, Saoussen Krid, Mieczyslaw Litwin, Lukasz Obrycki, Fabio Paglialonga, Bruno Ranchin, Charlotte Samaille, Franz Schaefer, Claus Peter Schmitt, Brankica Spasojevic, Constantinos J. Stefanidis, Maria Van Dyck, Koen Van Hoeck, Laure Collard, Sunny Eloot and Rukshana Shroffadd Show full author list remove Hide full author list
Toxins 2019, 11(4), 235; https://doi.org/10.3390/toxins11040235 - 24 Apr 2019
Cited by 22 | Viewed by 4122
Abstract
Protein-bound uremic toxins (PBUTs) play a role in the multisystem disease that children on hemodialysis (HD) are facing, but little is known about their levels and protein binding (%PB). In this study, we evaluated the levels and %PB of six PBUTs cross-sectionally in [...] Read more.
Protein-bound uremic toxins (PBUTs) play a role in the multisystem disease that children on hemodialysis (HD) are facing, but little is known about their levels and protein binding (%PB). In this study, we evaluated the levels and %PB of six PBUTs cross-sectionally in a large pediatric HD cohort (n = 170) by comparing these with healthy and non-dialysis chronic kidney disease (CKD) stage 4–5 (n = 24) children. In parallel β2-microglobulin (β2M) and uric acid (UA) were evaluated. We then explored the impact of age and residual kidney function on uremic toxin levels and %PB using analysis of covariance and Spearman correlation coefficients (rs). We found higher levels of β2M, p-cresyl glucuronide (pCG), hippuric acid (HA), indole acetic acid (IAA), and indoxyl sulfate (IxS) in the HD compared to the CKD4–5 group. In the HD group, a positive correlation between age and pCG, HA, IxS, and pCS levels was shown. Residual urine volume was negatively correlated with levels of β2M, pCG, HA, IAA, IxS, and CMPF (rs −0.2 to −0.5). In addition, we found overall lower %PB of PBUTs in HD versus the CKD4–5 group, and showed an age-dependent increase in %PB of IAA, IxS, and pCS. Furhtermore, residual kidney function was overall positively correlated with %PB of PBUTs. In conclusion, residual kidney function and age contribute to PBUT levels and %PB in the pediatric HD population. Full article
(This article belongs to the Special Issue Disposition of Uremic Toxins: The Challenges in Uremia)
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12 pages, 269 KiB  
Article
Association of Uremic Toxins and Inflammatory Markers with Physical Performance in Dialysis Patients
by Maja Pajek, Alexander Jerman, Joško Osredkar, Jadranka Buturović Ponikvar and Jernej Pajek
Toxins 2018, 10(10), 403; https://doi.org/10.3390/toxins10100403 - 1 Oct 2018
Cited by 13 | Viewed by 3503
Abstract
Association of higher serum levels of uremic toxins and inflammatory markers with poorer physical performance is understudied. We measured the six-minute walk test (6MWT), 10 repetition sit-to-stand test (STS-10), handgrip strength (HGS), and Human Activity Profile (HAP) questionnaire score in 90 prevalent hemodialysis [...] Read more.
Association of higher serum levels of uremic toxins and inflammatory markers with poorer physical performance is understudied. We measured the six-minute walk test (6MWT), 10 repetition sit-to-stand test (STS-10), handgrip strength (HGS), and Human Activity Profile (HAP) questionnaire score in 90 prevalent hemodialysis patents, with low comorbidity to reduce the potential confounding of concomitant disease. Midweek pre-dialysis serum levels of asymmetric dimethyl-arginine (ADMA), β2-microglobulin (B2M), high-sensitivity C-reactive protein (hs-CRP), indoxyl sulfate (IS), insulin-like growth factor 1 (IGF-1), interleukin 6 (IL-6), myostatin, and urea were analyzed as predictor parameters of physical performance measures in adjusted models. Serum levels of most measured toxins were not significantly related to performance, except for ADMA, which was significantly related to poorer performance in the STS-10 test (B = 0.11 ± 0.03 s, p < 0.01). Higher hs-CRP was associated with poorer results in the 6MWT (B = −2.6 ± 0.97 m, p < 0.01) and a lower HAP score (B = −0.36 ± 0.14, p = 0.01). There were no other significant associations found. We conclude that inflammation may be a more important pathway to physical impediment than uremic toxemia. This suggests that there is a large physical rehabilitation potential in non-inflamed uremic patients. Full article
(This article belongs to the Special Issue Disposition of Uremic Toxins: The Challenges in Uremia)
12 pages, 254 KiB  
Article
Effects of Dietary Arginine, Ornithine, and Zeolite Supplementation on Uremic Toxins in Cats
by Nadine Paßlack and Jürgen Zentek
Toxins 2018, 10(5), 206; https://doi.org/10.3390/toxins10050206 - 18 May 2018
Cited by 3 | Viewed by 4256
Abstract
To test if arginine and ornithine, both components of the Krebs-Henseleit cycle, or zeolite, a potential ammonium absorber, can modulate the excretion of harmful bacterial metabolites, intestinal microbial protein fermentation was stimulated by feeding a high-protein (60.3%) diet as a single daily meal [...] Read more.
To test if arginine and ornithine, both components of the Krebs-Henseleit cycle, or zeolite, a potential ammonium absorber, can modulate the excretion of harmful bacterial metabolites, intestinal microbial protein fermentation was stimulated by feeding a high-protein (60.3%) diet as a single daily meal to 10 adult cats. The diet was supplemented without or with arginine (+50, 75, 100% compared to arginine in the basal diet), ornithine (+100, 150, 200% compared to arginine in the basal diet), or zeolite (0.125, 0.25, 0.375 g/kg body weight/day). The cats received each diet for 11 days. Urine, feces, and blood were collected during the last 4 days. Arginine and ornithine enhanced the postprandial increase of blood urea, but renal urea excretion was not increased. Zeolite decreased renal ammonium excretion and fecal biogenic amines. The data indicate an increased detoxification rate of ammonia by arginine and ornithine supplementation. However, as urea was not increasingly excreted, detrimental effects on renal function cannot be excluded. Zeolite had beneficial effects on the intestinal nitrogen metabolism, which should be further evaluated in diseased cats. Clinical studies should investigate whether dietary arginine and ornithine might improve hepatic ammonia detoxification or could be detrimental for renal function. Full article
(This article belongs to the Special Issue Disposition of Uremic Toxins: The Challenges in Uremia)

Review

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18 pages, 696 KiB  
Review
Emerging Roles of Aryl Hydrocarbon Receptors in the Altered Clearance of Drugs during Chronic Kidney Disease
by Tacy Santana Machado, Claire Cerini and Stéphane Burtey
Toxins 2019, 11(4), 209; https://doi.org/10.3390/toxins11040209 - 7 Apr 2019
Cited by 14 | Viewed by 4572
Abstract
Chronic kidney disease (CKD) is a major public health problem, since 300,000,000 people in the world display a glomerular filtration rate (GFR) below 60 mL/min/1.73m2. Patients with CKD have high rates of complications and comorbidities. Thus, they require the prescription of [...] Read more.
Chronic kidney disease (CKD) is a major public health problem, since 300,000,000 people in the world display a glomerular filtration rate (GFR) below 60 mL/min/1.73m2. Patients with CKD have high rates of complications and comorbidities. Thus, they require the prescription of numerous medications, making the management of patients very complex. The prescription of numerous drugs associated with an altered renal- and non-renal clearance makes dose adjustment challenging in these patients, with frequent drug-related adverse events. However, the mechanisms involved in this abnormal drug clearance during CKD are not still well identified. We propose here that the transcription factor, aryl hydrocarbon receptor, which is the cellular receptor for indolic uremic toxins, could worsen the metabolism and the excretion of drugs in CKD patients. Full article
(This article belongs to the Special Issue Disposition of Uremic Toxins: The Challenges in Uremia)
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20 pages, 741 KiB  
Review
FGF23, Biomarker or Target?
by Cristian Rodelo-Haad, Rafael Santamaria, Juan R. Muñoz-Castañeda, M. Victoria Pendón-Ruiz de Mier, Alejandro Martin-Malo and Mariano Rodriguez
Toxins 2019, 11(3), 175; https://doi.org/10.3390/toxins11030175 - 22 Mar 2019
Cited by 44 | Viewed by 10613
Abstract
Fibroblast growth factor 23 (FGF23) plays a key role in the complex network between the bones and other organs. Initially, it was thought that FGF23 exclusively regulated phosphate and vitamin D metabolism; however, recent research has demonstrated that an excess of FGF23 has [...] Read more.
Fibroblast growth factor 23 (FGF23) plays a key role in the complex network between the bones and other organs. Initially, it was thought that FGF23 exclusively regulated phosphate and vitamin D metabolism; however, recent research has demonstrated that an excess of FGF23 has other effects that may be detrimental in some cases. The understanding of the signaling pathways through which FGF23 acts in different organs is crucial to develop strategies aiming to prevent the negative effects associated with high FGF23 levels. FGF23 has been described to have effects on the heart, promoting left ventricular hypertrophy (LVH); the liver, leading to production of inflammatory cytokines; the bones, inhibiting mineralization; and the bone marrow, by reducing the production of erythropoietin (EPO). The identification of FGF23 receptors will play a remarkable role in future research since its selective blockade might reduce the adverse effects of FGF23. Patients with chronic kidney disease (CKD) have very high levels of FGF23 and may be the population suffering from the most adverse FGF23-related effects. The general population, as well as kidney transplant recipients, may also be affected by high FGF23. Whether the association between FGF23 and clinical events is causal or casual remains controversial. The hypothesis that FGF23 could be considered a therapeutic target is gaining relevance and may become a promising field of investigation in the future. Full article
(This article belongs to the Special Issue Disposition of Uremic Toxins: The Challenges in Uremia)
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