P1286THE RELATIONSHIP BETWEEN PROTEIN-BOUND UREMIC TOXINS AND TARGET CARDIOVASCULAR PROTEINS IN HEMODIALYSIS PATIENTS

Abstract Background and Aims Uremic toxins are crucial non-traditional risk factors for cardiovascular disease in patients with chronic kidney disease (CKD). Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) were associated with all-cause and cardiovascular mortality in CKD patients, but possible mechanisms have not been fully elucidated. Herein, we explored the association between protein-bound uremic toxins and 181 cardiovascular-specific proteins in patients receiving hemodialysis (HD). Method In the discovery phase, we investigated associations between circulating free form IS and PCS and cardiovascular-specific protein levels quantified by a proximity extension assay of 333 stable HD patients with correction for multiple testing. In the second phase, the independent association was assessed using multivariable-adjusted models. The associations of IS or PCS with cardiovascular-specific proteins levels on a continuous scale were also evaluated. Results Free form IS was negatively associated with six proteins (C-C motif chemokine 15, complement component C1q receptor, perlecan, bleomycin hydrolase, cluster of differentiation 166 antigen, and signaling lymphocytic activation molecule family member 5) and positively associated with one protein (fibroblast growth factor 23). Free form PCS was negatively associated with three proteins (C-C motif chemokine 15, complement component C1q receptor, and interleukin-1 receptor-like 2). Adjusting the multivariable models for classical cardiovascular risk factors at baseline yielded similar results. Conclusion Protein-bound uremic toxins (IS and PCS) were associated with several cardiovascular-specific proteins involved in cell adhesion, endothelial barrier function, inflammation, complement system, and phosphate homeostasis. Multiplex proteomics appears to be a promising way to explore novel aspects of uremic toxin pathophysiology.

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The relationship of indoxyl sulfate and p-cresyl sulfate with target cardiovascular proteins in hemodialysis patients

Scientific Reports ◽

10.1038/s41598-021-83383-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ping-Hsun Wu ◽

Yi-Ting Lin ◽

Yi-Wen Chiu ◽

Gabriel Baldanzi ◽

Jiun-Chi Huang ◽

...

Keyword(s):

Hemodialysis Patients ◽

Complement Component ◽

Uremic Toxins ◽

Indoxyl Sulfate ◽

Free Form ◽

Negatively Associated ◽

Coronary Syndrome ◽

Increased Risk ◽

Related Proteins ◽

The Relationship

AbstractProtein-bound uremic toxins (Indoxyl sulfate [IS] and p-cresyl sulfate [PCS]) are both associated with cardiovascular (CV) and all-cause mortality in subjects with chronic kidney disease (CKD). Possible mechanisms have not been elucidated. In hemodialysis patients, we investigated the relationship between the free form of IS and PCS and 181 CV-related proteins. First, IS or PCS concentrations were checked, and high levels were associated with an increased risk of acute coronary syndrome (ACS) in 333 stable HD patients. CV proteins were further quantified by a proximity extension assay. We examined associations between the free form protein-bound uremic toxins and the quantified proteins with correction for multiple testing in the discovery process. In the second step, the independent association was evaluated by multivariable-adjusted models. We rank the CV proteins related to protein-bound uremic toxins by bootstrapped confidence intervals and ascending p-value. Six proteins (signaling lymphocytic activation molecule family member 5, complement component C1q receptor, C–C motif chemokine 15 [CCL15], bleomycin hydrolase, perlecan, and cluster of differentiation 166 antigen) were negatively associated with IS. Fibroblast growth factor 23 [FGF23] was the only CV protein positively associated with IS. Three proteins (complement component C1q receptor, CCL15, and interleukin-1 receptor-like 2) were negatively associated with PCS. Similar findings were obtained after adjusting for classical CV risk factors. However, only higher levels of FGF23 was related to increased risk of ACS. In conclusion, IS and PCS were associated with several CV-related proteins involved in endothelial barrier function, complement system, cell adhesion, phosphate homeostasis, and inflammation. Multiplex proteomics seems to be a promising way to discover novel pathophysiology of the uremic toxin.

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The Association of Polyunsaturated Fatty Acid δ-5-Desaturase Activity with Risk Factors for Type 2 Diabetes Is Dependent on Plasma ApoB-Lipoproteins in Overweight and Obese Adults

Journal of Nutrition ◽

10.1093/jn/nxy238 ◽

2018 ◽

Vol 149 (1) ◽

pp. 57-67 ◽

Cited By ~ 1

Author(s):

Valérie Lamantia ◽

Simon Bissonnette ◽

Viviane Provost ◽

Marie Devaux ◽

Yannick Cyr ◽

...

Keyword(s):

Risk Factors ◽

Type 2 Diabetes ◽

Fatty Acids ◽

Interleukin 1 ◽

Area Under The Curve ◽

Plasma Phospholipid ◽

Pooled Analysis ◽

Second Phase ◽

Obese Adults

ABSTRACTBackgroundδ-5 and δ-6 desaturases (D5D and D6D) catalyze the endogenous conversion of n–3 (ω-3) and n–6 (ω-6) polyunsaturated fatty acids (PUFAs). Their activities are negatively and positively associated with type 2 diabetes (T2D), respectively, by unclear mechanisms. Elevated plasma apoB-lipoproteins (measured as plasma apoB), which can be reduced by n–3 PUFA intake, promote T2D risk factors.ObjectiveThe aim of this study was to test the hypothesis that the association of D5D and D6D activities with T2D risk factors is dependent on plasma apoB.MethodsThis is a pooled analysis of 2 populations recruited for 2 different metabolic studies. It is a post hoc analysis of baseline data of these subjects [n = 98; 60% women (postmenopausal); mean ± SD body mass index (in kg/m2): 32.8 ± 4.7; mean ± SD age: 57.6 ± 6.3 y]. Glucose-induced insulin secretion (GIIS) and insulin sensitivity (IS) were measured using Botnia clamps. Plasma clearance of a high-fat meal (600 kcal/m2, 66% fat) and white adipose tissue (WAT) function (storage of 3H-triolein-labeled substrate) were assessed in a subpopulation (n = 47). Desaturase activities were estimated from plasma phospholipid fatty acids. Associations were examined using Pearson and partial correlations.ResultsWhile both desaturase activities were positively associated with percentage of eicosapentaenoic acid, only D5D was negatively associated with plasma apoB (r = −0.30, P = 0.003). Association of D5D activity with second-phase GIIS (r = −0.23, P = 0.029), IS (r = 0.33, P = 0.015, in women) and 6-h area-under-the-curve (AUC6h) of plasma chylomicrons (apoB48, r = −0.47, P = 0.020, in women) was independent of age and adiposity, but was eliminated after adjustment for plasma apoB. D6D activity was associated in the opposite direction with GIIS (r = 0.24, P = 0.049), IS (r = −0.36, P = 0.004) and AUC6h chylomicrons (r = 0.52, P = 0.004), independent of plasma apoB. Both desaturases were associated with plasma interleukin-1-receptor antagonist (D5D: r = −0.45, P < 0.001 in women; D6D: r = −0.33, P = 0.007) and WAT function (trend for D5D: r = 0.30, P = 0.05; D6D: r = 0.39, P = 0.027) independent of any adjustment.ConclusionsAssociation of D5D activity with IS, lower GIIS, and plasma chylomicron clearance is dependent on plasma apoB in overweight and obese adults.

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Intestinal Chelators, Sorbants, and Gut-Derived Uremic Toxins

Toxins ◽

10.3390/toxins13020091 ◽

2021 ◽

Vol 13 (2) ◽

pp. 91

Author(s):

Solène M. Laville ◽

Ziad A. Massy ◽

Said Kamel ◽

Jean Marc Chillon ◽

Gabriel Choukroun ◽

...

Keyword(s):

Risk Factors ◽

Hemodialysis Patients ◽

Uremic Toxins ◽

Phosphate Binders ◽

Uremic Toxin ◽

Asian Countries ◽

Comorbidity Burden ◽

Major Nutrient ◽

Survival And Reproduction ◽

High Comorbidity

Chronic kidney disease (CKD) is a highly prevalent condition and is associated with a high comorbidity burden, polymedication, and a high mortality rate. A number of conventional and nonconventional risk factors for comorbidities and mortality in CKD have been identified. Among the nonconventional risk factors, uremic toxins are valuable therapeutic targets. The fact that some uremic toxins are gut-derived suggests that intestinal chelators might have a therapeutic effect. The phosphate binders used to prevent hyperphosphatemia in hemodialysis patients act by complexing inorganic phosphate in the gastrointestinal tract but might conceivably have a nonspecific action on gut-derived uremic toxins. Since phosphorous is a major nutrient for the survival and reproduction of bacteria, changes in its intestinal concentration may impact the gut microbiota’s activity and composition. Furthermore, AST-120 is an orally administered activated charcoal adsorbent that is widely used in Asian countries to specifically decrease uremic toxin levels. In this narrative review, we examine the latest data on the use of oral nonspecific and specific intestinal chelators to reduce levels of gut-derived uremic toxins.

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Protein-bound uremic toxins are associated with cognitive function among patients undergoing maintenance hemodialysis

Scientific Reports ◽

10.1038/s41598-019-57004-7 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 7

Author(s):

Yi-Ting Lin ◽

Ping-Hsun Wu ◽

Shih-Shin Liang ◽

Mwenya Mubanga ◽

Yuan-Han Yang ◽

...

Keyword(s):

Cognitive Function ◽

Cognitive Abilities ◽

Uremic Toxins ◽

Free Form ◽

Maintenance Hemodialysis ◽

Long Term Memory ◽

Negatively Associated ◽

Manipulation Language ◽

State Examination

AbstractPatients with chronic kidney disease have a greater risk of cognitive impairment. Cerebral uremic solute accumulation causes uremic encephalopathy; however, the association of protein-bound uremic toxins on cognitive function remains unclear. The present study aimed to investigate the association of two protein-bound uremic toxins, namely indoxyl sulfate (IS) and p-cresyl sulfate (PCS), on cognitive function in patients receiving hemodialysis (HD) for at least 90 days. Circulating free form IS and PCS were quantified by liquid chromatography/mass spectrometry. Mini-Mental State Examination (MMSE) and Cognitive Abilities Screening Instrument (CASI) were used to evaluate cognitive function. In total, 260 HD patients were recruited with a mean age of 58.1 ± 11.3 years, of which, 53.8% were men, 40% had diabetes, and 75.4% had hypertension. The analysis revealed that both free IS and free PCS were negatively associated with the CASI score and MMSE. After controlling for confounders, circulating free IS levels persisted to be negatively associated with MMSE scores [β = −0.62, 95% confidence interval (CI): −1.16 to −0.08] and CASI scores (β = −1.97, 95% CI: −3.78 to −0.16), mainly in the CASI domains of long-term memory, mental manipulation, language ability, and spatial construction. However, there was no correlation between free PCS and total MMSE or total CASI scores after controlling for confounders. In conclusion, circulating free form IS, but not PCS is associated with lower cognitive function test scores in HD patients. Thus, a further study is needed to evaluate whether a decrease in free IS levels can slow down cognitive decline in HD patients.

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Non-Traditional Cardiovascular Risk Markers in the Era of Established Major Risk Factors and Multiple Guidelines

Current Vascular Pharmacology ◽

10.2174/1570161116666180123112956 ◽

2019 ◽

Vol 17 (3) ◽

pp. 270-277 ◽

Cited By ~ 1

Author(s):

Thomas F. Whayne

Keyword(s):

Risk Factors ◽

Interleukin 1 ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

High Sensitivity ◽

Arterial Disease ◽

Good Evidence ◽

Ldl Particles ◽

Cv Disease ◽

Peripheral Arterial

The non-traditional cardiovascular (CV) risk factors that appear to be of most clinical interest include: apolipoprotein A (ApoA), apolipoprotein B (ApoB), high-sensitivity C-Reactive protein (hsCRP), homocysteine, interleukin 1 (IL1), lipoprotein (a) [Lp(a)], the density of low-density lipoprotein (LDL) particles, the LDL particle number, tissue/tumor necrosis factor-α (TNF-α) and uric acid. These non-traditional risk factors may be of value in adding further confirmation and attention to suspected significant CV risk. They can also provide a better understanding of current concepts of atherogenesis (e.g. various potential mechanisms associated with inflammation) as an etiology and in guiding current plus future therapies. In the mid-20th century, atherosclerosis and CV disease were considered mechanistic occurrences with essentially no attention to possible metabolic and molecular etiologies. Therefore, the only treatments then centered around mainly surgical procedures to try to improve blood flow, first with peripheral arterial disease (PAD) and later coronary artery disease (CAD). Now, failure to treat CV risk factors, especially where there is good evidence-based medicine, as in the case of statins for high CV risk patients, is considered medical negligence. Nevertheless, many problems remain to be solved regarding atherosclerosis prevention and treatment.

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Contribution of Gut Microbiota-Derived Uremic Toxins to the Cardiovascular System Mineralization

Toxins ◽

10.3390/toxins13040274 ◽

2021 ◽

Vol 13 (4) ◽

pp. 274

Author(s):

Iwona Filipska ◽

Agata Winiarska ◽

Monika Knysak ◽

Tomasz Stompór

Keyword(s):

Kidney Disease ◽

Gut Microbiota ◽

Mineral Content ◽

Uremic Toxins ◽

World Population ◽

Uremic Toxin ◽

Excess Morbidity ◽

The Media ◽

Cardio Vascular ◽

End Stage

Chronic kidney disease (CKD) affects more than 10% of the world population and leads to excess morbidity and mortality (with cardiovascular disease as a leading cause of death). Vascular calcification (VC) is a phenomenon of disseminated deposition of mineral content within the media layer of arteries preceded by phenotypic changes in vascular smooth muscle cells (VSMC) and/or accumulation of mineral content within the atherosclerotic lesions. Medial VC results in vascular stiffness and significantly contributes to increased cardio-vascular (CV) morbidity, whereas VC of plaques may rather increase their stability. Mineral and bone disorders of CKD (CKD-MBD) contribute to VC, which is further aggravated by accumulation of uremic toxins. Both CKD-MBD and uremic toxin accumulation affect not only patients with advanced CKD (glomerular filtration rate (GFR) less than 15 mL/min./1.72 m2, end-stage kidney disease) but also those on earlier stages of a disease. The key uremic toxins that contribute to VC, i.e., p-cresyl sulphate (PCS), indoxyl sulphate (IS) and trimethylamine-N-oxide (TMAO) originate from bacterial metabolism of gut microbiota. All mentioned toxins promote VC by several mechanisms, including: Transdifferentiation and apoptosis of VSMC, dysfunction of endothelial cells, oxidative stress, interaction with local renin–angiotensin–aldosterone system or miRNA profile modification. Several attractive methods of gut microbiota manipulations have been proposed in order to modify their metabolism and to limit vascular damage (and VC) triggered by uremic toxins. Unfortunately, to date no such method was demonstrated to be effective at the level of “hard” patient-oriented or even clinically relevant surrogate endpoints.

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Uremic Toxins and Frailty in Patients with Chronic Kidney Disease: A Molecular Insight

International Journal of Molecular Sciences ◽

10.3390/ijms22126270 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6270

Author(s):

Chia-Ter Chao ◽

Shih-Hua Lin

Keyword(s):

Chronic Kidney Disease ◽

Renal Function ◽

Kidney Disease ◽

Uremic Toxins ◽

Heme Oxygenase 1 ◽

Signal Pathways ◽

Uremic Toxin ◽

Nuclear Factor ◽

Cognitive Frailty ◽

Renal Function Decline

The accumulation of uremic toxins (UTs) is a prototypical manifestation of uremic milieu that follows renal function decline (chronic kidney disease, CKD). Frailty as a potential outcome-relevant indicator is also prevalent in CKD. The intertwined relationship between uremic toxins, including small/large solutes (phosphate, asymmetric dimethylarginine) and protein-bound ones like indoxyl sulfate (IS) and p-cresyl sulfate (pCS), and frailty pathogenesis has been documented recently. Uremic toxins were shown in vitro and in vivo to induce noxious effects on many organ systems and likely influenced frailty development through their effects on multiple preceding events and companions of frailty, such as sarcopenia/muscle wasting, cognitive impairment/cognitive frailty, osteoporosis/osteodystrophy, vascular calcification, and cardiopulmonary deconditioning. These organ-specific effects may be mediated through different molecular mechanisms or signal pathways such as peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), mitogen-activated protein kinase (MAPK) signaling, aryl hydrocarbon receptor (AhR)/nuclear factor-κB (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Runt-related transcription factor 2 (RUNX2), bone morphogenic protein 2 (BMP2), osterix, Notch signaling, autophagy effectors, microRNAs, and reactive oxygen species induction. Anecdotal clinical studies also suggest that frailty may further accelerate renal function decline, thereby augmenting the accumulation of UTs in affected individuals. Judging from these threads of evidence, management strategies aiming for uremic toxin reduction may be a promising approach for frailty amelioration in patients with CKD. Uremic toxin lowering strategies may bear the potential of improving patients’ outcomes and restoring their quality of life, through frailty attenuation. Pathogenic molecule-targeted therapeutics potentially disconnect the association between uremic toxins and frailty, additionally serving as an outcome-modifying approach in the future.

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A history of uremic toxicity and of the European Uremic Toxin Work Group (EUTox)

Clinical Kidney Journal ◽

10.1093/ckj/sfab011 ◽

2021 ◽

Cited By ~ 1

Author(s):

Raymond Vanholder ◽

Angel Argiles ◽

Joachim Jankowski ◽

Keyword(s):

Work Group ◽

Target Identification ◽

Kidney Injury ◽

Uremic Toxins ◽

Uremic Toxin ◽

Post Translational Modifications ◽

History Of ◽

Advanced Stages ◽

Uremic Syndrome

Abstract The uremic syndrome is a complex clinical picture developing in the advanced stages of chronic kidney disease (CKD) resulting in a myriad of complications and a high early mortality. This picture is to a significant extent defined by retention of metabolites and peptides that with a preserved kidney function are excreted or degraded by the kidneys. In as far as those solutes have a negative biological/biochemical impact, they are called uremic toxins. Here, we describe the historical evolution of the scientific knowledge about uremic toxins and the role played in this process by the European Uremic Toxin Work Group (EUTox) during the last two decades. The earliest knowledge about a uremic toxin goes back to the early 17th century when the existence of what later would appear to be urea was recognized. It cost about two further centuries to better define the role of urea and its link to kidney failure and one more century to identify the relevance of post-translational modifications caused by urea such as carbamoylation. The knowledge progressively extended, especially from 1980 on, by the identification of more and more toxins and their adverse biological/biochemical impact. Progress of knowledge was paralleled and impacted by evolution of dialysis strategies. The last two decades, when Insights grew exponentially, coincides with the foundation and activity of EUTox. In the final section we summarize the role and accomplishments of EUTox and the part it is likely to play in future action, which should be organized around focus points like biomarker and potential target identification, intestinal generation, toxicity mechanisms and their correction, kidney and extracorporeal removal, patient-oriented outcomes, and toxin characteristics in acute kidney injury and transplantation.

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Risk Factors for CKD Progression

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.07830520 ◽

2020 ◽

pp. CJN.07830520

Author(s):

Mary Hannan ◽

Sajid Ansari ◽

Natalie Meza ◽

Amanda H. Anderson ◽

Anand Srivastava ◽

...

Keyword(s):

Risk Factors ◽

Genome Wide Association Study ◽

Healthy Lifestyle ◽

Interdisciplinary Collaboration ◽

Fibroblast Growth Factor 23 ◽

Kidney Injury ◽

The United States ◽

Future Research ◽

Ckd Progression ◽

Factors Associated

The Chronic Renal Insufficiency Cohort (CRIC) Study is an ongoing, multicenter, longitudinal study of nearly 5500 adults with CKD in the United States. Over the past 10 years, the CRIC Study has made significant contributions to the understanding of factors associated with CKD progression. This review summarizes findings from longitudinal studies evaluating risk factors associated with CKD progression in the CRIC Study, grouped into the following six thematic categories: (1) sociodemographic and economic (sex, race/ethnicity, and nephrology care); (2) behavioral (healthy lifestyle, diet, and sleep); (3) genetic (apoL1, genome-wide association study, and renin-angiotensin-aldosterone system pathway genes); (4) cardiovascular (atrial fibrillation, hypertension, and vascular stiffness); (5) metabolic (fibroblast growth factor 23 and urinary oxalate); and (6) novel factors (AKI and biomarkers of kidney injury). Additionally, we highlight areas where future research is needed, and opportunities for interdisciplinary collaboration.

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Assessment of the Metabolic Pathways Associated With Glucose-Stimulated Biphasic Insulin Secretion

Endocrinology ◽

10.1210/en.2013-1805 ◽

2014 ◽

Vol 155 (5) ◽

pp. 1653-1666 ◽

Cited By ~ 23

Author(s):

Mei Huang ◽

Jamie W. Joseph

Keyword(s):

Insulin Secretion ◽

Time Course ◽

Tricarboxylic Acid Cycle ◽

Global Analysis ◽

Tricarboxylic Acid ◽

Second Phase ◽

Data Set ◽

Negatively Associated ◽

Biphasic Insulin ◽

Biphasic Insulin Secretion

Biphasic glucose-stimulated insulin secretion involves a rapid first phase followed by a prolonged second phase of insulin secretion. The biochemical pathways that control these 2 phases of insulin secretion are poorly defined. In this study, we used a gas chromatography mass spectroscopy-based metabolomics approach to perform a global analysis of cellular metabolism during biphasic insulin secretion. A time course metabolomic analysis of the clonal β-cell line 832/13 cells showed that glycolytic, tricarboxylic acid, pentose phosphate pathway, and several amino acids were strongly correlated to biphasic insulin secretion. Interestingly, first-phase insulin secretion was negatively associated with l-valine, trans-4-hydroxy-l-proline, trans-3-hydroxy-l-proline, dl-3-aminoisobutyric acid, l-glutamine, sarcosine, l-lysine, and thymine and positively with l-glutamic acid, flavin adenine dinucleotide, caprylic acid, uridine 5′-monophosphate, phosphoglycerate, myristic acid, capric acid, oleic acid, linoleic acid, and palmitoleic acid. Tricarboxylic acid cycle intermediates pyruvate, α-ketoglutarate, and succinate were positively associated with second-phase insulin secretion. Other metabolites such as myo-inositol, cholesterol, dl-3-aminobutyric acid, and l-norleucine were negatively associated metabolites with the second-phase of insulin secretion. These studies provide a detailed analysis of key metabolites that are either negatively or positively associated with biphasic insulin secretion. The insights provided by these data set create a framework for planning future studies in the assessment of the metabolic regulation of biphasic insulin secretion.

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