Association of Indoxyl Sulfate with Heart Failure among Patients on Hemodialysis

Cao, Xuesen; Chen, Jun; Zou, Jianzhou; Zhong, Yun‐Shi; Teng, Jie; Ji, Jun; Chen, Zhangwei; Z, Liu; Shen, Bo; Nie, Yuxin; Lv, Wen-lv; Fei, Xiang; Tan, Xiao; Ding, Xiaoqiang

doi:10.2215/cjn.04730514

Cited by 102 publications

(93 citation statements)

References 36 publications

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“…Plasma level of indoxyl sulfate (IS) was detected by ultra-performance liquid chromatography-mass spectrometry/mass spectrometry, as we described before [10]. …”

Section: Methodsmentioning

confidence: 99%

Low Plasma Hydrogen Sulfide Is Associated with Impaired Renal Function and Cardiac Dysfunction

et al. 2018

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Background: Chronic kidney disease (CKD) has been proposed to associate with decreased hydrogen sulfide (H₂S) level. Nevertheless, the role of H₂S in the pathogenesis of CKD has not been fully investigated. Our study aimed to investigate the plasma level of endogenous H₂S in patients with different stages of CKD, and to identify the role of H₂S in the progression of CKD and its relationship with cardiovascular diseases. Methods: A total of 157 non-dialysis CKD patients were recruited in our study, with 37 age- and sex-matched healthy individuals as control. Plasma concentration of H₂S was measured with spectrophotometry. Sulfhemoglobin, the integration of H₂S and hemoglobin, was characterized and measured by dual wavelength spectrophotometry. Serum levels of homocysteine (Hcy), cardiac troponin T (cTnT), and N-terminal pro B type natriuretic peptide were measured using automated analyzers. Conventional transthoracic echocardiography was performed and left ventricular ejection fraction (LVEF) was analyzed as a sensitive parameter of cardiac dysfunction. Results: The plasma H₂S level (μmol/L) in CKD patients was significantly lower than those in healthy controls (7.32 ± 4.02 vs. 14.11 ± 5.24 μmol/L, p < 0.01). Plasma H₂S level was positively associated with estimated glomerular filtration rate (eGFR; ρ = 0.577, p < 0.01) and negatively associated with plasma indoxyl sulfate concentration (ρ = –0.554, p < 0.01). The mRNA levels of cystathionine β-synthase and cystathionine γ-lyase, 2 catalytic enzymes of H₂S formation, were significantly lower in blood mononuclear cells of CKD patients with respect to controls; however, the mRNA level of 3-mercaptopyruvate sulfurtransferase, as another H₂S-producing enzyme, was significantly higher in CKD patients. The serum concentration of Hcy, acting as the substrate of H₂S synthetase, was higher in the CKD group (p < 0.01). Specifically, the content of serum Hcy in CKD stages 3–5 patients was significantly higher than that in CKD stages 1–2, indicating an increasing trend of serum Hcy with the decline of renal function. Examination of ultrasonic cardiogram revealed a negative correlation between plasma H₂S level and LVEF (ρ = –0.204, p < 0.05) in CKD patients. The H₂S level also correlated negatively with cTnT concentration (ρ = –0.249, p < 0.01). Conclusions: Plasma H₂S level decreased with the decline of eGFR, which may contribute to the cardiac dysfunction in CKD patients.

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“…Plasma level of indoxyl sulfate (IS) was detected by ultra-performance liquid chromatography-mass spectrometry/mass spectrometry, as we described before [10]. …”

Section: Methodsmentioning

confidence: 99%

Low Plasma Hydrogen Sulfide Is Associated with Impaired Renal Function and Cardiac Dysfunction

et al. 2018

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“…Oxidative stress from the accumulation of I3S has also been shown to increase the risk of cardiovascular disease in CDK patients through oxidative modification of low-density lipoproteins (Cao et al, 2015). The in vitro oxidation of low-density lipoproteins by indoxyl radicals has been shown to generate the AHR activator tryptanthrin (Praschberger et al, 2014).…”

Section: Host Metabolism Of Indolesmentioning

confidence: 99%

Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation

Hubbard¹,

Murray²,

Perdew³

2015

Drug Metab Dispos

488

432

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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor recognized for its role in xenobiotic metabolism. The physiologic function of AHR has expanded to include roles in immune regulation, organogenesis, mucosal barrier function, and the cell cycle. These functions are likely dependent upon ligandmediated activation of the receptor. High-affinity ligands of AHR have been classically defined as xenobiotics, such as polychlorinated biphenyls and dioxins. Identification of endogenous AHR ligands is key to understanding the physiologic functions of this enigmatic receptor. Metabolic pathways targeting the amino acid tryptophan and indole can lead to a myriad of metabolites, some of which are AHR ligands. Many of these ligands exhibit species selective preferential binding to AHR. The discovery of specific tryptophan metabolites as AHR ligands may provide insight concerning where AHR is activated in an organism, such as at the site of inflammation and within the intestinal tract.

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“…In CKD patients, serum indoxyl sulphate levels have been shown to have an inverse relationship with kidney function and a direct relationship with aortic calcification, pulse-wave velocity, first heart failure event, and all-cause and cardiovascular mortality [75][76][77]. The mortality association remained after adjustment for age, gender, diabetes mellitus, albumin, hemoglobin, phosphorus levels, and aortic calcification [75].…”

Section: Cardiovascular Disease and Mortalitymentioning

confidence: 99%

Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins

et al. 2018

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In chronic kidney disease (CKD), influx of urea and other retained toxins exerts a change in the gut microbiome. There is decreased number of beneficial bacteria that produce short-chain fatty acids, an essential nutrient for the colonic epithelium, concurrent with an increase in bacteria that produce uremic toxins such as indoxyl sulphate, p-cresyl sulphate, and trimethylamine-N-oxide (TMAO). Due to intestinal wall inflammation and degradation of intercellular tight junctions, gut-derived uremic toxins translocate into the bloodstream and exert systemic effects. In this review, we discuss the evidence supporting a role for gut-derived uremic toxins in promoting multiorgan dysfunction via inflammatory, oxidative stress, and apoptosis pathways. End-organ effects include vascular calcification, kidney fibrosis, anemia, impaired immune system, adipocyte dysfunction with insulin resistance, and low turnover bone disease. Higher blood levels of gut-derived uremic toxins are associated with increased cardiovascular events and mortality in the CKD population. Clinical trials that have examined interventions to trap toxic products or reverse gut microbial dysbiosis via oral activated charcoal AST-120, prebiotics and probiotics have not shown impact on cardiovascular or survival outcomes but were limited by sample size and short trials. In summary, the gut microbiome is a major contributor to adverse cardiovascular outcomes and progression of CKD.

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Association of Indoxyl Sulfate with Heart Failure among Patients on Hemodialysis

Cited by 102 publications

References 36 publications

Low Plasma Hydrogen Sulfide Is Associated with Impaired Renal Function and Cardiac Dysfunction

Low Plasma Hydrogen Sulfide Is Associated with Impaired Renal Function and Cardiac Dysfunction

Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation

Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins

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