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Special Issue "Uremic Toxins"

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A special issue of Toxins (ISSN 2072-6651).

Deadline for manuscript submissions: closed (30 November 2013)

Special Issue Editor

Guest Editor
Prof. Dr. Joachim Jankowski

Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Medizinische Klinik IV, Hindenburgdamm 30, 12200 Berlin, Germany
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Fax: +49 30 450 525923

Special Issue Information

Dear Colleagues,

Uremia is a clinical syndrome associated with fluid, electrolyte, and hormone imbalances and metabolic abnormalities, which develop in parallel with deterioration of renal function. The term uremia, which literally means urine in the blood, was first used by Piorry to describe the clinical condition associated with renal failure [1].Uremia is a medical disorder characterized by excessive waste products and urea, which is a waste product of urine, in the blood. As chronic renal failure progresses, a gradual dose-dependent dysfunction of most organ systems occurs [2]. This ultimately results in the malfunctioning of the entire body, and as symptoms become more and more prominent, survival and quality of life can only be maintained by replacing kidney function by dialysis or transplantation.

Currently, chronic renal failure as well as uremia is legitimately considered as a major public-health problem. Since only a part of chronic renal failure patients progress to uremia and on the other hand the therapy of uremia is complex and expensive, (A) identification of mediators of chronic renal failure and uremia using molecular, proteomic, metabolomic, genomic and functional genomics studies, (B) identification of the underlying mechanisms of chronic renal failure and uremia, (C) validation of biomarkers for detecting chronic renal failure patients at risk of progression and (D) development of appropriate medical responses (new drug targets and/or new treatment strategies) are of great importance both for the prognosis and early intervention of renal failure patients.

Therefore, the aim of this special issue "Uremic Toxins" is to make a contribution to the clarification of the mechanisms of uremia, and to develop new therapeutic approaches.

Prof. Dr. Joachim Jankowski
Guest Editor

References

1. Piorry, P.; l'Heritier, D. Traite des Alterations du Sang; Bury & JB Bailliere: Paris, France, 1840.
2. Vanholder, R.; De Smet, R. Pathophysiologic effects of uremic retention solutes. J. Am. Soc. Nephrol. 1999, 10, 1815–1823.

Submission

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a 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 1000 CHF (Swiss Francs).

Keywords

  • chronic renal failure
  • uremic syndrome
  • retention solutes
  • uremic toxins
  • kidney function
  • cardiovascular diseases
  • glomerular filtration rate
  • uremia

Published Papers (17 papers)

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Research

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Open AccessArticle An Optical Method for Serum Calcium and Phosphorus Level Assessment during Hemodialysis
Toxins 2015, 7(3), 719-727; doi:10.3390/toxins7030719
Received: 18 November 2014 / Revised: 26 January 2015 / Accepted: 11 February 2015 / Published: 27 February 2015
Cited by 2 | PDF Full-text (776 KB) | HTML Full-text | XML Full-text
Abstract
Survival among hemodialysis patients is disturbingly low, partly because vascular calcification (VC) and cardiovascular disease are highly prevalent. Elevated serum phosphorus (P) and calcium (Ca) levels play an essential role in the formation of VC events. The purpose of the current study was
[...] Read more.
Survival among hemodialysis patients is disturbingly low, partly because vascular calcification (VC) and cardiovascular disease are highly prevalent. Elevated serum phosphorus (P) and calcium (Ca) levels play an essential role in the formation of VC events. The purpose of the current study was to reveal optical monitoring possibilities of serum P and Ca values during dialysis. Twenty-eight patients from Tallinn (Estonia) and Linköping (Sweden) were included in the study. The serum levels of Ca and P on the basis of optical information, i.e., absorbance and fluorescence of the spent dialysate (optical method) were assessed. Obtained levels were compared in means and SD. The mean serum level of Ca was 2.54 ± 0.21 and 2.53 ± 0.19 mmol/L; P levels varied between 1.08 ± 0.51 and 1.08 ± 0.48 mmol/L, measured in the laboratory and estimated by the optical method respectively. The levels achieved were not significantly different (p = 0.5). The Bland-Altman 95% limits of agreement between the two methods varied from −0.19 to 0.19 for Ca and from −0.37 to 0.37 in the case of P. In conclusion, optical monitoring of the spent dialysate for assessing the serum levels of Ca and P during dialysis seems to be feasible and could offer valuable and continuous information to medical staff. Full article
(This article belongs to the Special Issue Uremic Toxins)
Open AccessArticle Binding Affinity and Capacity for the Uremic Toxin Indoxyl Sulfate
Toxins 2014, 6(2), 416-429; doi:10.3390/toxins6020416
Received: 9 November 2013 / Revised: 13 January 2014 / Accepted: 14 January 2014 / Published: 24 January 2014
Cited by 7 | PDF Full-text (553 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Protein binding prevents uremic toxins from removal by conventional extracorporeal therapies leading to accumulation in maintenance dialysis patients. Weakening of the protein binding may enhance the dialytic elimination of these toxins. In ultrafiltration and equilibrium dialysis experiments, different measures to modify the plasma
[...] Read more.
Protein binding prevents uremic toxins from removal by conventional extracorporeal therapies leading to accumulation in maintenance dialysis patients. Weakening of the protein binding may enhance the dialytic elimination of these toxins. In ultrafiltration and equilibrium dialysis experiments, different measures to modify the plasma binding affinity and capacity were tested: (i), increasing the sodium chloride (NaCl) concentration to achieve a higher ionic strength; (ii), increasing the temperature; and (iii), dilution. The effects on the dissociation constant KD and the protein bound fraction of the prototypical uremic toxin indoxyl sulfate (IS) in plasma of healthy and uremic individuals were studied. Binding of IS corresponded to one site binding in normal plasma. KD increased linearly with the NaCl concentration between 0.15 (KD = 13.2 ± 3.7 µM) and 0.75 M (KD = 56.2 ± 2.0 µM). Plasma dilution further reduced the protein bound toxin fraction by lowering the protein binding capacity of the plasma. Higher temperatures also decreased the protein bound fraction of IS in human plasma. Increasing the NaCl concentration was effective to weaken the binding of IS also in uremic plasma: the protein bound fraction decreased from 89% ± 3% to 81% ± 3% at 0.15 and 0.75 M NaCl, respectively. Dilution and increasing the ionic strength and temperature enhance the free fraction of IS allowing better removal of the substance during dialysis. Applied during clinical dialysis, this may have beneficial effects on the long-term outcome of maintenance dialysis patients. Full article
(This article belongs to the Special Issue Uremic Toxins)
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Open AccessArticle Methylglyoxal (MG) and Cerebro-Renal Interaction: Does Long-Term Orally Administered MG Cause Cognitive Impairment in Normal Sprague-Dawley Rats?
Toxins 2014, 6(1), 254-269; doi:10.3390/toxins6010254
Received: 24 October 2013 / Revised: 24 December 2013 / Accepted: 31 December 2013 / Published: 7 January 2014
Cited by 3 | PDF Full-text (1174 KB) | HTML Full-text | XML Full-text
Abstract
Methylglyoxal (MG), one of the uremic toxins, is a highly reactive alpha-dicarbonyl compound. Recent clinical studies have demonstrated the close associations of cognitive impairment (CI) with plasma MG levels and presence of kidney dysfunction. Therefore, the present study aims to examine whether MG
[...] Read more.
Methylglyoxal (MG), one of the uremic toxins, is a highly reactive alpha-dicarbonyl compound. Recent clinical studies have demonstrated the close associations of cognitive impairment (CI) with plasma MG levels and presence of kidney dysfunction. Therefore, the present study aims to examine whether MG is a direct causative substance for CI development. Eight-week-old male Sprague-Dawley (SD) rats were divided into two groups: control (n = 9) and MG group (n = 10; 0.5% MG in drinking water), and fed a normal diet for 12 months. Cognitive function was evaluated by two behavioral tests (object exploration test and radial-arm maze test) in early (4–6 months of age) and late phase (7–12 months of age). Serum MG was significantly elevated in the MG group (495.8 ± 38.1 vs. 244.8 ± 28.2 nM; p < 0.001) at the end of study. The groups did not differ in cognitive function during the course of study. No time-course differences were found in oxidative stress markers between the two groups, while, antioxidants such as glutathione peroxidase and superoxide dismutase activities were significantly increased in the MG group compared to the control. Long-term MG administration to rats with normal kidney function did not cause CI. A counter-balanced activation of the systemic anti-oxidant system may offset the toxicity of MG in this model. Pathogenetic significance of MG for CI requires further investigation. Full article
(This article belongs to the Special Issue Uremic Toxins)
Open AccessArticle Neurological Disorders in a Murine Model of Chronic Renal Failure
Toxins 2014, 6(1), 180-193; doi:10.3390/toxins6010180
Received: 29 October 2013 / Revised: 19 December 2013 / Accepted: 23 December 2013 / Published: 3 January 2014
Cited by 1 | PDF Full-text (695 KB) | HTML Full-text | XML Full-text
Abstract
Cardiovascular disease is highly prevalent in patients with chronic renal failure (CRF). However, data on the impact of CRF on the cerebral circulatory system are scarce—despite the fact that stroke is the third most common cause of cardiovascular death in people with CRF.
[...] Read more.
Cardiovascular disease is highly prevalent in patients with chronic renal failure (CRF). However, data on the impact of CRF on the cerebral circulatory system are scarce—despite the fact that stroke is the third most common cause of cardiovascular death in people with CRF. In the present study, we examined the impact of CRF on behavior (anxiety), recognition and ischemic stroke severity in a well-defined murine model of CRF. We did not observe any significant increases between CRF mice and non-CRF mice in terms of anxiety. In contrast, CRF mice showed lower levels of anxiety in some tests. Recognition was not impaired (vs. controls) after 6 weeks of CRF but was impaired after 10 weeks of CRF. Chronic renal failure enhances the severity of ischemic stroke, as evaluated by the infarct volume size in CRF mice after 34 weeks of CRF. Furthermore, neurological test results in non-CRF mice tended to improve in the days following ischemic stroke, whereas the results in CRF mice tended to worsen. In conclusion, we showed that a murine model of CRF is suitable for evaluating uremic toxicity and the associated neurological disorders. Our data confirm the role of uremic toxicity in the genesis of neurological abnormalities (other than anxiety). Full article
(This article belongs to the Special Issue Uremic Toxins)
Open AccessArticle Association between Free Light Chain Levels, and Disease Progression and Mortality in Chronic Kidney Disease
Toxins 2013, 5(11), 2058-2073; doi:10.3390/toxins5112058
Received: 24 September 2013 / Revised: 28 October 2013 / Accepted: 29 October 2013 / Published: 8 November 2013
Cited by 5 | PDF Full-text (326 KB) | HTML Full-text | XML Full-text
Abstract
Immunoglobulin free light chains (FLCs) form part of the middle molecule group of uremic toxins. Accumulation of FLCs has been observed in patients with chronic kidney disease (CKD). The aim of the present study was to measure FLC levels in patients at different
[...] Read more.
Immunoglobulin free light chains (FLCs) form part of the middle molecule group of uremic toxins. Accumulation of FLCs has been observed in patients with chronic kidney disease (CKD). The aim of the present study was to measure FLC levels in patients at different CKD stages and to assess putative associations between FLC levels on one hand and biochemical/clinical parameters and mortality on the other. One hundred and forty patients at CKD stages 2-5D were included in the present study. Routine clinical biochemistry assays and assays for FLC kappa (κ) and lambda (λ) and other uremic toxins were performed. Vascular calcification was evaluated using radiological techniques. The enrolled patients were prospectively monitored for mortality. Free light chain κ and λ levels were found to be elevated in CKD patients (especially in those on hemodialysis). Furthermore, FLC κ and λ levels were positively correlated with inflammation, aortic calcification and the levels of various uremic toxins levels. A multivariate linear regression analysis indicated that FLC κ and λ levels were independently associated with CKD stages and β2 microglobulin levels. Elevated FLC κ and λ levels appeared to be associated with mortality. However, this association disappeared after adjustment for a propensity score including age, CKD stage and aortic calcification. In conclusion, our results indicate that FLC κ and λ levels are elevated in CKD patients and are associated with inflammation, vascular calcification and levels of other uremic toxins. The observed link between elevated FLC levels and mortality appears to depend on other well-known factors. Full article
(This article belongs to the Special Issue Uremic Toxins)
Open AccessArticle Effects of Decreased Vitamin D and Accumulated Uremic Toxin on Human CYP3A4 Activity in Patients with End-Stage Renal Disease
Toxins 2013, 5(8), 1475-1485; doi:10.3390/toxins5081475
Received: 28 June 2013 / Revised: 1 August 2013 / Accepted: 6 August 2013 / Published: 19 August 2013
Cited by 5 | PDF Full-text (278 KB) | HTML Full-text | XML Full-text
Abstract
In patients with end-stage renal disease, not only renal clearance but also hepatic clearance is known to be impaired. For instance, the concentration of erythromycin, a substrate of cytochrome P450 3A4 (CYP3A4), has been reported to be elevated in patients with end-stage renal
[...] Read more.
In patients with end-stage renal disease, not only renal clearance but also hepatic clearance is known to be impaired. For instance, the concentration of erythromycin, a substrate of cytochrome P450 3A4 (CYP3A4), has been reported to be elevated in patients with end-stage renal disease. The purpose of this study is to elucidate the reason for the decrease in hepatic clearance in patients with end-stage renal disease. Deproteinized pooled sera were used to assess the effects of low-molecular-weight uremic toxins on CYP3A4 activity in human liver microsomes and human LS180 cells. Four uremic toxins (3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, hippuric acid, indole-3-acetic acid, and 3-indoxyl sulfate) present at high concentrations in uremic serum were also studied. Simultaneous treatment of uremic serum (less than 10%) or uremic toxins did not affect testosterone 6β-hydroxylation in human liver microsomes. On the other hand, pretreatment of each serum activates CYP3A4 in LS180 cells, and the increased CYP3A4 activity in uremic serum-treated cells was smaller than normal serum-treated cells. In addition, CYP3A4 and CYP24A1 mRNA levels also increased in LS180 cells exposed to normal serum, and this effect was reduced in uremic serum-treated cells and in cells exposed to uremic serum added to normal serum. Furthermore, addition of 1,25-dihydroxyvitamin D to uremic serum partially restored the serum effect on CYP3A4 expression. The present study suggests that the decrease of 1,25-dihydroxyvitamin D and the accumulation of uremic toxins contributed to the decreased hepatic clearance of CYP3A4 substrates in patients with end-stage renal disease. Full article
(This article belongs to the Special Issue Uremic Toxins)
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Open AccessArticle A Metabolomic Approach to Clarifying the Effect of AST-120 on 5/6 Nephrectomized Rats by Capillary Electrophoresis with Mass Spectrometry (CE-MS)
Toxins 2012, 4(11), 1309-1322; doi:10.3390/toxins4111309
Received: 18 July 2012 / Revised: 19 September 2012 / Accepted: 26 October 2012 / Published: 14 November 2012
Cited by 9 | PDF Full-text (708 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The oral adsorbent AST-120 is composed of spherical carbon particles and has an adsorption ability for certain small-molecular-weight compounds that accumulate in patients with chronic kidney disease (CKD). So far, very few compounds are known to be adsorbed by AST-120 in vivo.
[...] Read more.
The oral adsorbent AST-120 is composed of spherical carbon particles and has an adsorption ability for certain small-molecular-weight compounds that accumulate in patients with chronic kidney disease (CKD). So far, very few compounds are known to be adsorbed by AST-120 in vivo. To examine the effect of AST-120 in vivo, we comprehensively evaluated the plasma concentrations of 146 compounds (61 anions and 85 cations) in CKD model rats, with or without four weeks of treatment with AST-120. By capillary electrophoresis with mass spectrometry, we identified 6 anions and 17 cations that were significantly decreased by AST-120 treatment. In contrast, we also identified 2 cations that were significantly increased by AST-120. Among them, 4 anions, apart from indoxyl sulfate and hippurate, and 19 cations were newly identified in this study. The plasma levels of N-acetyl-neuraminate, 4-pyridoxate, 4-oxopentanoate, glycine, γ-guanidinobutyrate, N-γ-ethylglutamine, allantoin, cytosine, 5-methylcytosine and imidazole-4-acetate were significantly increased in the CKD model compared with the sham-operated group, and were significantly decreased by AST-120 treatment. Therefore, these 10 compounds could be added as uremic compounds that indicate the effect of AST-120 treatment. This study provides useful information not only for identifying the indicators of AST-120, but also for clarifying changes in the metabolic profile by AST-120 treatment in the clinical setting. Full article
(This article belongs to the Special Issue Uremic Toxins)
Open AccessArticle Do Only Small Uremic Toxins, Chromophores, Contribute to the Online Dialysis Dose Monitoring by UV Absorbance?
Toxins 2012, 4(10), 849-861; doi:10.3390/toxins4100849
Received: 30 June 2012 / Revised: 25 September 2012 / Accepted: 27 September 2012 / Published: 18 October 2012
Cited by 7 | PDF Full-text (768 KB) | HTML Full-text | XML Full-text
Abstract
The aim of this work was to evaluate the contributions of the main chromophores to the total UV absorbance of the spent dialysate and to assess removal dynamics of these solutes during optical on-line dialysis dose monitoring. High performance chromatography was used to
[...] Read more.
The aim of this work was to evaluate the contributions of the main chromophores to the total UV absorbance of the spent dialysate and to assess removal dynamics of these solutes during optical on-line dialysis dose monitoring. High performance chromatography was used to separate and quantify UV-absorbing solutes in the spent dialysate sampled at the start and at the end of dialysis sessions. Chromatograms were monitored at 210, 254 and 280 nm routinely and full absorption spectra were registered between 200 and 400 nm. Nearly 95% of UV absorbance originates from solutes with high removal ratio, such as uric acid. The contributions of different solute groups vary at different wavelengths and there are dynamical changes in contributions during the single dialysis session. However, large standard deviation of the average contribution values within a series of sessions indicates remarkable differences between individual treatments. A noteworthy contribution of Paracetamol and its metabolites to the total UV absorbance was determined at all three wavelengths. Contribution of slowly dialyzed uremic solutes, such as indoxyl sulfate, was negligible. Full article
(This article belongs to the Special Issue Uremic Toxins)
Open AccessArticle Protein-Bound Uremic Toxins: New Insight from Clinical Studies
Toxins 2011, 3(7), 911-919; doi:10.3390/toxins3070911
Received: 29 April 2011 / Revised: 28 June 2011 / Accepted: 5 July 2011 / Published: 20 July 2011
Cited by 34 | PDF Full-text (394 KB) | HTML Full-text | XML Full-text
Abstract
The uremic syndrome is attributed to the progressive retention of a large number of compounds which, under normal conditions, are excreted by healthy kidneys. The compounds are called uremic toxins when they interact negatively with biological functions. The present review focuses on a
[...] Read more.
The uremic syndrome is attributed to the progressive retention of a large number of compounds which, under normal conditions, are excreted by healthy kidneys. The compounds are called uremic toxins when they interact negatively with biological functions. The present review focuses on a specific class of molecules, namely the family of protein-bound uremic toxins. Recent experimental studies have shown that protein-bound toxins are involved not only in the progression of chronic kidney disease (CKD), but also in the generation and aggravation of cardiovascular disease. Two protein-bound uremic retention solutes, namely indoxyl sulfate and p-cresyl sulfate, have been shown to play a prominent role. However, although these two molecules belong to the same class of molecules, exert toxic effects on the cardiovascular system in experimental animals, and accumulate in the serum of patients with CKD they may have different clinical impacts in terms of cardiovascular disease and other complications. The principal aim of this review is to evaluate the effect of p-cresyl sulfate and indoxyl sulfate retention on CKD patient outcomes, based on recent clinical studies. Full article
(This article belongs to the Special Issue Uremic Toxins)
Open AccessArticle Comparative 1H NMR Metabolomic Urinalysis of People Diagnosed with Balkan Endemic Nephropathy, and Healthy Subjects, in Romania and Bulgaria: A Pilot Study
Toxins 2011, 3(7), 815-833; doi:10.3390/toxins3070815
Received: 30 May 2011 / Revised: 22 June 2011 / Accepted: 28 June 2011 / Published: 4 July 2011
Cited by 4 | PDF Full-text (640 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
1H NMR spectroscopy of urine has been applied to exploring metabolomic differences between people diagnosed with Balkan endemic nephropathy (BEN), and treated by haemodialysis, and those without overt renal disease in Romania and Bulgaria. Convenience sampling was made from patients receiving haemodialysis
[...] Read more.
1H NMR spectroscopy of urine has been applied to exploring metabolomic differences between people diagnosed with Balkan endemic nephropathy (BEN), and treated by haemodialysis, and those without overt renal disease in Romania and Bulgaria. Convenience sampling was made from patients receiving haemodialysis in hospital and healthy controls in their village. Principal component analysis clustered healthy controls from both countries together. Bulgarian BEN patients clustered separately from controls, though in the same space. However, Romanian BEN patients not only also clustered away from controls but also clustered separately from the BEN patients in Bulgaria. Notably, the urinary metabolomic data of two people sampled as Romanian controls clustered within the Romanian BEN group. One of these had been suspected of incipient symptoms of BEN at the time of selection as a ‘healthy’ control. This implies, at first sight, that metabolomic analysis can be predictive of impending morbidity before conventional criteria can diagnose BEN. Separate clustering of BEN patients from Romania and Bulgaria could indicate difference in aetiology of this particular silent renal atrophy in different geographic foci across the Balkans. Full article
(This article belongs to the Special Issue Uremic Toxins)
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Open AccessArticle 4-Pyridone-3-carboxamide-1-β-d-ribonucleoside Triphosphate (4PyTP), a Novel NAD+ Metabolite Accumulating in Erythrocytes of Uremic Children: A Biomarker for a Toxic NAD+ Analogue in Other Tissues?
Toxins 2011, 3(6), 520-537; doi:10.3390/toxins3060520
Received: 25 March 2011 / Revised: 13 May 2011 / Accepted: 31 May 2011 / Published: 7 June 2011
Cited by 6 | PDF Full-text (568 KB) | HTML Full-text | XML Full-text
Abstract
We have identified a novel nucleotide, 4-pyridone 3/5-carboxamide ribonucleoside triphosphate (4PyTP), which accumulates in human erythrocytes during renal failure. Using plasma and erythrocyte extracts obtained from children with chronic renal failure we show that the concentration of 4PyTP is increased, as well as
[...] Read more.
We have identified a novel nucleotide, 4-pyridone 3/5-carboxamide ribonucleoside triphosphate (4PyTP), which accumulates in human erythrocytes during renal failure. Using plasma and erythrocyte extracts obtained from children with chronic renal failure we show that the concentration of 4PyTP is increased, as well as other soluble NAD+ metabolites (nicotinamide, N1-methylnicotinamide and 4Py-riboside) and the major nicotinamide metabolite N1-methyl-2-pyridone-5-carboxamide (2PY), with increasing degrees of renal failure. We noted that 2PY concentration was highest in the plasma of haemodialysis patients, while 4PyTP was highest in erythrocytes of children undergoing peritoneal dialysis: its concentration correlated closely with 4Py-riboside, an authentic precursor of 4PyTP, in the plasma. In the dialysis patients, GTP concentration was elevated: similar accumulation was noted previously, as a paradoxical effect in erythrocytes during treatment with immunosuppressants such as ribavirin and mycophenolate mofetil, which deplete GTP through inhibition of IMP dehydrogenase in nucleated cells such as lymphocytes. We predict that 4Py-riboside and 4Py-nucleotides bind to this enzyme and alter its activity. The enzymes that regenerate NAD+ from nicotinamide riboside also convert the drugs tiazofurin and benzamide riboside into NAD+ analogues that inhibit IMP dehydrogenase more effectively than the related ribosides: we therefore propose that the accumulation of 4PyTP in erythrocytes during renal failure is a marker for the accumulation of a related toxic NAD+ analogue that inhibits IMP dehydrogenase in other cells. Full article
(This article belongs to the Special Issue Uremic Toxins)
Open AccessArticle 1H NMR Spectroscopy-Based Metabolomic Assessment of Uremic Toxicity, with Toxicological Outcomes, in Male Rats Following an Acute, Mid-Life Insult from Ochratoxin A
Toxins 2011, 3(6), 504-519; doi:10.3390/toxins3060504
Received: 13 March 2011 / Revised: 19 May 2011 / Accepted: 23 May 2011 / Published: 26 May 2011
Cited by 6 | PDF Full-text (223 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Overt response to a single 6.25 mg dose of ochratoxin A (OTA) by oral gavage to 15 months male rats was progressive loss of weight during the following four days. Lost weight was restored within one month and animals had a normal life-span
[...] Read more.
Overt response to a single 6.25 mg dose of ochratoxin A (OTA) by oral gavage to 15 months male rats was progressive loss of weight during the following four days. Lost weight was restored within one month and animals had a normal life-span without OTA-related terminal disease. Decline in plasma OTA concentration only commenced four days after dosing, while urinary excretion of OTA and ochratoxin alpha was ongoing. During a temporary period of acute polyuria, a linear relationship between urine output and creatinine concentration persisted. Elimination of other common urinary solutes relative to creatinine was generally maintained during the polyuria phase, except that phosphate excretion increased temporarily. 1H NMR metabolomic analysis of urine revealed a progressive cyclic shift in the group principal components data cluster from before dosing, throughout the acute insult phase, and returning almost completely to normality when tested six months later. Renal insult by OTA was detected by 1H NMR within a day of dosing, as the most sensitive early indicator. Notable biomarkers were trimethylamine N-oxide and an aromatic urinary profile dominated by phenylacetylglycine. Tolerance of such a large acute insult by OTA, assessed by rat natural lifetime outcomes, adds a new dimension to toxicology of this xenobiotic. Full article
(This article belongs to the Special Issue Uremic Toxins)
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Review

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Open AccessReview Uremic Toxins and Lipases in Haemodialysis: A Process of Repeated Metabolic Starvation
Toxins 2014, 6(5), 1505-1511; doi:10.3390/toxins6051505
Received: 11 March 2014 / Revised: 11 April 2014 / Accepted: 14 April 2014 / Published: 30 April 2014
Cited by 3 | PDF Full-text (182 KB) | HTML Full-text | XML Full-text
Abstract
Severe kidney disease results in retention of uremic toxins that inhibit key enzymes for lipid breakdown such as lipoprotein lipase (LPL) and hepatic lipase (HL). For patients in haemodialysis (HD) and peritoneal dialysis (PD) the LPL activity is only about half of that
[...] Read more.
Severe kidney disease results in retention of uremic toxins that inhibit key enzymes for lipid breakdown such as lipoprotein lipase (LPL) and hepatic lipase (HL). For patients in haemodialysis (HD) and peritoneal dialysis (PD) the LPL activity is only about half of that of age and gender matched controls. Angiopoietin, like protein 3 and 4, accumulate in the uremic patients. These factors, therefore, can be considered as uremic toxins. In animal experiments it has been shown that these factors inhibit the LPL activity. To avoid clotting of the dialysis circuit during HD, anticoagulation such as heparin or low molecular weight heparin are added to the patient. Such administration will cause a prompt release of the LPL and HL from its binding sites at the endothelial surface. The liver rapidly degrades the release plasma compound of LPL and HL. This results in a lack of enzyme to degrade triglycerides during the later part of the HD and for another 3–4 h. PD patients have a similar baseline level of lipases but are not exposed to the negative effect of anticoagulation. Full article
(This article belongs to the Special Issue Uremic Toxins)
Open AccessReview The Aryl Hydrocarbon Receptor-Activating Effect of Uremic Toxins from Tryptophan Metabolism: A New Concept to Understand Cardiovascular Complications of Chronic Kidney Disease
Toxins 2014, 6(3), 934-949; doi:10.3390/toxins6030934
Received: 25 November 2013 / Revised: 19 February 2014 / Accepted: 24 February 2014 / Published: 4 March 2014
Cited by 23 | PDF Full-text (262 KB) | HTML Full-text | XML Full-text
Abstract
Patients with chronic kidney disease (CKD) have a higher risk of cardiovascular diseases and suffer from accelerated atherosclerosis. CKD patients are permanently exposed to uremic toxins, making them good candidates as pathogenic agents. We focus here on uremic toxins from tryptophan metabolism because
[...] Read more.
Patients with chronic kidney disease (CKD) have a higher risk of cardiovascular diseases and suffer from accelerated atherosclerosis. CKD patients are permanently exposed to uremic toxins, making them good candidates as pathogenic agents. We focus here on uremic toxins from tryptophan metabolism because of their potential involvement in cardiovascular toxicity: indolic uremic toxins (indoxyl sulfate, indole-3 acetic acid, and indoxyl-β-d-glucuronide) and uremic toxins from the kynurenine pathway (kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and quinolinic acid). Uremic toxins derived from tryptophan are endogenous ligands of the transcription factor aryl hydrocarbon receptor (AhR). AhR, also known as the dioxin receptor, interacts with various regulatory and signaling proteins, including protein kinases and phosphatases, and Nuclear Factor-Kappa-B. AhR activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin and some polychlorinated biphenyls is associated with an increase in cardiovascular disease in humans and in mice. In addition, this AhR activation mediates cardiotoxicity, vascular inflammation, and a procoagulant and prooxidant phenotype of vascular cells. Uremic toxins derived from tryptophan have prooxidant, proinflammatory, procoagulant, and pro-apoptotic effects on cells involved in the cardiovascular system, and some of them are related with cardiovascular complications in CKD. We discuss here how the cardiovascular effects of these uremic toxins could be mediated by AhR activation, in a “dioxin-like” effect. Full article
(This article belongs to the Special Issue Uremic Toxins)
Open AccessReview Protein-Bound Uremic Toxins: New Culprits of Cardiovascular Events in Chronic Kidney Disease Patients
Toxins 2014, 6(2), 665-678; doi:10.3390/toxins6020665
Received: 11 December 2013 / Revised: 5 February 2014 / Accepted: 11 February 2014 / Published: 20 February 2014
Cited by 22 | PDF Full-text (529 KB) | HTML Full-text | XML Full-text
Abstract
Chronic kidney disease (CKD) has been considered a major risk factor for cardiovascular diseases. Although great advances have recently been made in the pathophysiology and treatment of cardiovascular diseases, CKD remains a major global health problem. Moreover, the occurrence rates of cardiovascular events
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Chronic kidney disease (CKD) has been considered a major risk factor for cardiovascular diseases. Although great advances have recently been made in the pathophysiology and treatment of cardiovascular diseases, CKD remains a major global health problem. Moreover, the occurrence rates of cardiovascular events among CKD patients increase even in cases in which patients undergo hemodialysis, and the mechanisms underlying the so-called “cardiorenal syndrome” are not clearly understood. Recently, small-molecule uremic toxins have been associated with cardiovascular mortality in CKD and/or dialysis patients. These toxins range from small uncharged solutes to large protein-bound structures. In this review, we focused on protein-bound uremic toxins, such as indoxyl sulfate and p-cresyl sulfate, which are poorly removed by current dialysis techniques. Several studies have demonstrated that protein-bound uremic toxins, especially indoxyl sulfate, induce vascular inflammation, endothelial dysfunction, and vascular calcification, which may explain the relatively poor prognosis of CKD and dialysis patients. The aim of this review is to provide novel insights into the effects of indoxyl sulfate and p-cresyl sulfate on the pathogenesis of atherosclerosis. Full article
(This article belongs to the Special Issue Uremic Toxins)
Open AccessReview From the Gastrointestinal Tract (GIT) to the Kidneys: Live Bacterial Cultures (Probiotics) Mediating Reductions of Uremic Toxin Levels via Free Radical Signaling
Toxins 2013, 5(11), 2042-2057; doi:10.3390/toxins5112042
Received: 2 September 2013 / Revised: 4 November 2013 / Accepted: 4 November 2013 / Published: 7 November 2013
Cited by 17 | PDF Full-text (253 KB) | HTML Full-text | XML Full-text
Abstract
A host of compounds are retained in the body of uremic patients, as a consequence of progressive renal failure. Hundreds of compounds have been reported to be retention solutes and many have been proven to have adverse biological activity, and recognized as uremic
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A host of compounds are retained in the body of uremic patients, as a consequence of progressive renal failure. Hundreds of compounds have been reported to be retention solutes and many have been proven to have adverse biological activity, and recognized as uremic toxins. The major mechanistic overview considered to contribute to uremic toxin overload implicates glucotoxicity, lipotoxicity, hexosamine, increased polyol pathway activity and the accumulation of advanced glycation end-products (AGEs). Until recently, the gastrointestinal tract (GIT) and its associated micro-biometabolome was a neglected factor in chronic disease development. A systematic underestimation has been to undervalue the contribution of GIT dysbiosis (a gut barrier-associated abnormality) whereby low-level pro-inflammatory processes contribute to chronic kidney disease (CKD) development. Gut dysbiosis provides a plausible clue to the origin of systemic uremic toxin loads encountered in clinical practice and may explain the increasing occurrence of CKD. In this review, we further expand a hypothesis that posits that environmentally triggered and maintained microbiome perturbations drive GIT dysbiosis with resultant uremia. These subtle adaptation responses by the GIT microbiome can be significantly influenced by probiotics with specific metabolic properties, thereby reducing uremic toxins in the gut. The benefit translates to a useful clinical treatment approach for patients diagnosed with CKD. Furthermore, the role of reactive oxygen species (ROS) in different anatomical locales is highlighted as a positive process. Production of ROS in the GIT by the epithelial lining and the commensal microbe cohort is a regulated process, leading to the formation of hydrogen peroxide which acts as an essential second messenger required for normal cellular homeostasis and physiological function. Whilst this critical review has focused on end-stage CKD (type 5), our aim was to build a plausible hypothesis for the administration of probiotics with or without prebiotics for the early treatment of kidney disease. We postulate that targeting healthy ROS production in the gut with probiotics may be more beneficial than any systemic antioxidant therapy (that is proposed to nullify ROS) for the prevention of kidney disease progression. The study and understanding of health-promoting probiotic bacteria is in its infancy; it is complex and intellectually and experimentally challenging. Full article
(This article belongs to the Special Issue Uremic Toxins)
Open AccessReview Immune Dysfunction in Uremia—An Update
Toxins 2012, 4(11), 962-990; doi:10.3390/toxins4110962
Received: 6 August 2012 / Revised: 26 September 2012 / Accepted: 8 October 2012 / Published: 24 October 2012
Cited by 28 | PDF Full-text (301 KB) | HTML Full-text | XML Full-text
Abstract
Kidney dysfunction leads to disturbed renal metabolic activities and to impaired glomerular filtration, resulting in the retention of toxic solutes affecting all organs of the body. Cardiovascular disease (CVD) and infections are the main causes for the increased occurrence of morbidity and mortality
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Kidney dysfunction leads to disturbed renal metabolic activities and to impaired glomerular filtration, resulting in the retention of toxic solutes affecting all organs of the body. Cardiovascular disease (CVD) and infections are the main causes for the increased occurrence of morbidity and mortality among patients with chronic kidney disease (CKD). Both complications are directly or indirectly linked to a compromised immune defense. The specific coordinated roles of polymorphonuclear leukocytes (PMNLs), monocytes/macrophages, lymphocytes and antigen-presenting cells (APCs) in maintaining an efficient immune response are affected. Their normal response can be impaired, giving rise to infectious diseases or pre-activated/primed, leading to inflammation and consequently to CVD. Whereas the coordinated removal via apoptosis of activated immune cells is crucial for the resolution of inflammation, inappropriately high apoptotic rates lead to a diminished immune response. In uremia, the balance between pro- and anti-inflammatory and between pro- and anti-apoptotic factors is disturbed. This review summarizes the interrelated parameters interfering with the immune response in uremia, with a special focus on the non-specific immune response and the role of uremic toxins. Full article
(This article belongs to the Special Issue Uremic Toxins)

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