• Effectiveness
• Gut
• Inflammation
• Microbiota
• Peritoneal dialysis
• Probiotics
• Treatment

• dyslipidemia
• outcomes
• peritoneal dialysis
• peritoneal membrane
• treatment

• Humans
• Renal Insufficiency, Chronic/therapy
• Renal Insufficiency, Chronic/complications
• Renal Insufficiency, Chronic/physiopathology
• Gastrointestinal Diseases/therapy
• Gastrointestinal Diseases/etiology
• Renal Dialysis/adverse effects
• Quality of Life
• Probiotics/therapeutic use
• Gastrointestinal Microbiome/physiology

• R01 DK110871 NIDDK NIH HHS
• K23DK122015 NIDDK NIH HHS
• P30 AR072581 NIAMS NIH HHS
• K23 DK122015 NIDDK NIH HHS
• UL1 TR002529 NCATS NIH HHS
• T32 DK120524 NIDDK NIH HHS
• K23DK122015 NIDDK NIH HHS
• T32 DK120524 NIDDK NIH HHS

• Calcium acetate
• Chronic kidney disease
• Gut microbiome
• Hemodialysis
• Phosphate binders
• Sucroferric oxyhydroxide

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.

• chronic kidney disease
• phosphate binders
• uremic toxins

Chronic kidney disease (CKD) afflicts more than 500 million people worldwide and is one of the fastest growing global causes of mortality. When glomerular filtration rate begins to fall, uremic toxins accumulate in the serum and significantly increase the risk of death from cardiovascular disease and other causes. Several of the most harmful uremic toxins are produced by the gut microbiota. Furthermore, many such toxins are protein-bound and are therefore recalcitrant to removal by dialysis. We review the derivation and pathological mechanisms of gut-derived, protein-bound uremic toxins (PBUTs). We further outline the emerging relationship between kidney disease and gut dysbiosis, including the bacterial taxa altered, the regulation of microbial uremic toxin-producing genes, and their downstream physiological and neurological consequences. Finally, we discuss gut-targeted therapeutic strategies employed to reduce PBUTs. We conclude that targeting the gut microbiota is a promising approach for the treatment of CKD by blocking the serum accumulation of PBUTs that cannot be eliminated by dialysis.

• gut-kidney axis
• intestinal microbiota
• protein-bound uremic toxins

• Animals
• Bacteria/metabolism
• Bacterial Toxins/metabolism
• Disease Progression
• Dysbiosis
• Gastrointestinal Microbiome
• Humans
• Protein Binding
• Renal Dialysis
• Renal Insufficiency, Chronic/metabolism
• Renal Insufficiency, Chronic/microbiology
• Renal Insufficiency, Chronic/therapy
• Uremia/metabolism
• Uremia/microbiology
• Uremia/therapy

• R01 GM135218 NIGMS NIH HHS
• R01 GM137286 NIGMS NIH HHS
• T32 GM135095 NIGMS NIH HHS

• Calcium/therapeutic use
• Chelating Agents/therapeutic use
• Gastrointestinal Tract/drug effects
• Humans
• Hyperphosphatemia/prevention & control
• Kidney Failure, Chronic/complications
• Phosphates/metabolism
• Sevelamer/therapeutic use

• P30 AR072581 NIAMS NIH HHS
• R01 DK110871 NIDDK NIH HHS
• T32 AR007581 NIAMS NIH HHS
• K01 DK102864 NIDDK NIH HHS
• UL1 TR002529 NCATS NIH HHS
• T32 DK120524 NIDDK NIH HHS
• R01 DK100306 NIDDK NIH HHS
• T32 AR065971 NIAMS NIH HHS

• Chronic kidney disease
• ESRD
• Hemodialysis
• Hyperphosphatemia
• Microbiome
• Phosphorus
• Uremic toxins

• Biosolids
• SLE-LTP
• m-cresol
• o-cresol
• p-cresol

• Brazil
• Chemical Fractionation/methods
• Cresols/analysis
• Cresols/chemistry
• Cresols/isolation & purification
• Gas Chromatography-Mass Spectrometry/methods
• Isomerism
• Limit of Detection
• Reproducibility of Results
• Sewage/analysis
• Temperature
• Waste Disposal, Fluid

High serum levels of gut-derived uremic toxins, especially p-cresyl sulfate (pCS), indoxyl sulfate (IS) and indole acetic acid (IAA), have been linked to adverse outcomes in patients with chronic kidney disease (CKD). Sevelamer carbonate could represent an interesting option to limit the elevation of gut-derived uremic toxins. The aim of the present study was to evaluate the adsorptive effect of sevelamer carbonate on different gut-derived protein-bound uremic toxins or their precursors in vitro, and its impact on the serum levels of pCS, IS and IAA in patients with CKD stage 3b/4. For the in vitro experiments, IAA, p-cresol (precursor of pCS) and indole (precursor of IS), each at a final concentration of 1 or 10 µg/mL, were incubated in centrifugal 30 kDa filter devices with 3 or 15 mg/mL sevelamer carbonate in phosphate-buffered saline at a pH adjusted to 6 or 8. Then, samples were centrifuged and free uremic toxins in the filtrates were analyzed. As a control experiment, the adsorption of phosphate was also evaluated. Additionally, patients with stage 3b/4 CKD (defined as an eGFR between 15 and 45 mL/min per 1.73 m²) were included in a multicenter, double-blind, placebo-controlled, randomized clinical trial. The participants received either placebo or sevelamer carbonate (4.8 g) three times a day for 12 weeks. The concentrations of the toxins and their precursors were measured using a validated high-performance liquid chromatography method with a diode array detector. In vitro, regardless of the pH and concentration tested, sevelamer carbonate did not show adsorption of indole and p-cresol. Conversely, with 10 µg/mL IAA, use of a high concentration of sevelamer carbonate (15 mg/mL) resulted in a significant toxin adsorption both at pH 8 (mean reduction: 26.3 ± 3.4%) and pH 6 (mean reduction: 38.7 ± 1.7%). In patients with CKD stage 3b/4, a 12-week course of treatment with sevelamer carbonate was not associated with significant decreases in serum pCS, IS and IAA levels (median difference to baseline levels: −0.12, 0.26 and −0.06 µg/mL in the sevelamer group vs. 1.97, 0.38 and 0.05 µg/mL in the placebo group, respectively). Finally, in vitro, sevelamer carbonate was capable of chelating a gut-derived uremic toxin IAA but not p-cresol and indole, the precursors of pCS and IS in the gut. In a well-designed clinical study of patients with stage 3b/4 CKD, a 12-week course of treatment with sevelamer carbonate was not associated with significant changes in the serum concentrations of pCS, IS and IAA.

• sevelamer
• uremic toxins

• Adsorption
• Aged
• Chelating Agents/administration & dosage
• Chelating Agents/chemistry
• Cresols/blood
• Cresols/chemistry
• Double-Blind Method
• Female
• Gastrointestinal Tract/chemistry
• Gastrointestinal Tract/metabolism
• Humans
• Indican/blood
• Indican/chemistry
• Indoleacetic Acids/blood
• Indoleacetic Acids/chemistry
• Male
• Middle Aged
• Renal Insufficiency, Chronic/blood
• Renal Insufficiency, Chronic/drug therapy
• Sevelamer/administration & dosage
• Sevelamer/chemistry
• Sulfuric Acid Esters/blood
• Sulfuric Acid Esters/chemistry
• Toxins, Biological/blood
• Uremia

• Cardiovascular risk
• Chronic kidney disease
• Sevelamer
• p-Cresol

• Prebiotic
• kidney transplantation
• p-Cresol
• probiotic
• synbiotic
• uremic toxins

Advanced glycation end products (AGEs) have been related to the pathogenesis of cardiovascular diseases (CVD), chronic kidney disease (CKD) and diabetes mellitus. We sought to investigate the binding capacity of sevelamer to both AGEs and uremic serum in vitro and then test this pharmaceutical effect as a potential vascular anti-inflammatory strategy.

AGEs were prepared by albumin glycation and characterized by absorbance and electrophoresis. Human endothelial cells were incubated in culture media containing AGEs and uremic serum with or without sevelamer. Receptor for advanced glycation end product (RAGE) expression was evaluated through immunocytochemistry and western blot to explore the interactions between AGEs and the endothelium. Inflammatory and endothelial dysfunction biomarkers, such as interleukin 6 (IL-6) and IL-8, monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1) and serum amyloid A (SAA) were also measured in cell supernatant. The chemotactic property of the supernatant was evaluated.

AGEs significantly induced the expression of RAGE, inflammatory and endothelial activation biomarkers [IL-6, (P < 0.005); IL-8, MCP-1, PAI-1 and SAA (P < 0.001)] and monocyte chemotaxis as compared with controls. In addition, AGEs increased the levels of inflammatory biomarkers, which were observed after 6 h of endothelial cell incubation with uremic serum [IL-6 (P < 0.001) IL-8, MCP-1 and PAI-1 (P < 0.05)]. On the other hand, after 6 h of endothelial cell treatment with sevelamer, RAGE expression (P < 0.05) and levels of inflammatory biomarkers [IL-6 and IL-8 (P < 0.001), MCP-1 (P < 0.01), PAI-1 and SAA (P < 0.005)] significantly decreased compared with the AGEs/uremic serum treatment alone.

Sevelamer decreased both endothelial expression of RAGE and endothelial dysfunction biomarkers, induced by AGEs, and uremic serum. Further studies are necessary for a better understanding of the potential protective role of sevelamer on uremic serum and AGEs-mediated endothelial dysfunction.

• AGEs
• chronic kidney disease
• endothelial dysfunction
• inflammation
• sevelamer
• uremic serum

Beside the phosphate binding effect, non-calcium non-aluminum phosphate binder, namely sevelamer hydrochloride (SH), has many other effects in dialysis patients. It can absorb many other compounds, decrease low-density lipoprotein cholesterol (LDL-C) level, and attenuate the progression of vascular calcification; it has been reported to have anti-inflammatory effect. However, it is not clear whether it has any effect on uremic toxins, i.e. serum indoxyl sulfate (IS) and p-cresyl sulfate, (PCS) in hemodialysis (HD) patients. This study was carried out to appraise the effect of sevelamer on serum IS and PCS in HD patients.

Five adult HD patients from a single medical center were enrolled in this study; these patients were treated with 800 mg of sevelamer thrice per day for 3 months; a series of biochemical parameters, serum IS and PCS were monitored concurrently.

There was a significant reduction in the mean level of phosphate from 7.20 ± 0.70 mg/dL (mean ± SD) before treatment to 5.40 ± 0.50 mg/dL (mean ± SD) after treatment, total cholesterol from 151.00 ± 37.40 mg/dL (mean ± SD) before treatment to 119.20 ± 29.40 mg/dL (mean ± SD) after treatment, and PCS from 31.30 ± 10.60 mg/L (mean ± SD) before treatment to 19.70 ± 10.50 mg/L (mean ± SD) after treatment. On the contrary, this treatment had no effect on IS.

A statistically significant reduction of serum phosphate and PCS in HD patients treated with SH suggests that beside the action of lowering serum phosphate, sevelamer may have an important role in the treatment of uremic syndrome by decreasing the uremic toxin.

• Hemodialysis
• Indoxyl sulfate
• P-cresyl sulfate
• Sevelamer hydrochloride

Sevelamer is a phosphate binder widely used in chronic kidney disease (CKD) patients. Sevelamer, as well as other resin-based binders, can crystallize leading to the formation of concretions. Sevelamer crystals (SC) have been associated with gastrointestinal (GI) mucosal injury. We describe three new cases of GI lesions associated with SC and review previously reported cases.

We describe three new cases of GI lesions associated with SC and review previously reported cases.

We found 16 previously reported cases of SC-induced GI lesions. The mean patient age was 61 years (interquartile range 51.5–71.75), 62.5% were females and 10 patients were diabetic. In 13 cases, SC was found inside the GI mucosa. Six patients had history of major abdominal surgery. GI bleeding was the most common clinical symptom (n = 7), with three patients presenting with acute abdomen requiring surgical intervention. Although, SC-induced lesions were observed in all GI segments, intestine was involved in 81% of the cases. Endoscopic examination revealed mainly erosions and ulcerations (n = 7) and pseudoinflammatory polyps (n = 5). No association between sevelamer doses and the severity of GI lesions was found. However, diabetics patients seemed to develop GI lesions with smaller doses of sevelamer as compared with non-diabetic patients, in spite of their fewer GI comorbidities.

SC-induced GI lesions should be considered in CKD patients treated with sevelamer who present GI symptoms, especially lower GI bleeding, once other causes have been ruled out. Diabetics seem more prone to develop SC- associated GI lesions. Sevelamer therapy should be avoided if possible in patients with a history of major abdominal surgery or chronic constipation, because of the high risk of serious GI complications.

• chronic kidney disease
• crystals
• gastrointestinal lesions
• hyperphosphataemia
• sevelamer

• Efectos pleiotrópicos
• Fósforo
• Gut
• Inflamación e intestino
• Inflammation
• Phosphate
• Pleiotropic effects
• Sevelamer

• Anticholesteremic Agents/pharmacology
• Anticholesteremic Agents/therapeutic use
• Bone and Bones/drug effects
• Calcinosis/drug therapy
• Chelating Agents/pharmacology
• Chelating Agents/therapeutic use
• Endothelium, Vascular/drug effects
• Endotoxins/pharmacokinetics
• Fibroblast Growth Factor-23
• Fibroblast Growth Factors/metabolism
• Glycation End Products, Advanced/metabolism
• Humans
• Inflammation
• Intestinal Absorption/drug effects
• Minerals/metabolism
• Oxidative Stress/drug effects
• Phosphorus/metabolism
• Renal Insufficiency, Chronic/drug therapy
• Renal Insufficiency, Chronic/metabolism
• Sevelamer/pharmacology
• Sevelamer/therapeutic use
• Signal Transduction/drug effects
• Uremia/drug therapy
• Uremia/metabolism
• Vascular Diseases/drug therapy

• cardiovascular mortality
• chronic kidney disease
• colestilan
• hyperlipidemia
• hyperphosphatemia
• phosphate binders
• sevelamer

• Animals
• Chagas Disease/complications
• Chagas Disease/metabolism
• Cresols/metabolism
• Female
• Metabolic Networks and Pathways/physiology
• Metabolome/physiology
• Metabolomics
• Mice
• Mice, Inbred BALB C
• Myocarditis/etiology
• Myocarditis/metabolism
• Sulfuric Acid Esters/metabolism
• Trypanosoma cruzi

• Chronic kidney disease
• Synbiotic
• p-cresol

• Aged
• Cresols/blood
• Disease Progression
• Double-Blind Method
• Female
• Glomerular Filtration Rate
• Humans
• Intestines/microbiology
• Kidney Failure, Chronic/blood
• Kidney Failure, Chronic/therapy
• Male
• Middle Aged
• Pilot Projects
• Synbiotics

The risk of cardiovascular mortality among patients with end-stage renal disease is several times higher than general population. Arterial calcification, a marker of atherosclerosis and a predictor of cardiovascular mortality, is common in chronic kidney disease (CKD). The presence of traditional cardiovascular risk factors such as diabetes, hypertension, hyperlipidemia, and advanced age cannot fully explain the high prevalence of atherosclerosis and arterial calcification. Other factors specific to CKD such as hyperphosphatemia, excess of calcium, high dose active vitamin D and prolonged dialysis vintage play important roles in the development of arterial calcification. Due to the significant health risk, it is prudent to attempt to lower arterial calcification burden in CKD. Treatment of hyperlipidemia with statin has failed to lower atherosclerotic and arterial calcification burden. Data on diabetes and blood pressure controls as well as smoking cessation on cardiovascular outcomes in CKD population are limited. Currently available treatment options include non-calcium containing phosphate binders, low dose active vitamin D, calcimimetic agent and perhaps bisphosphonates, vitamin K and sodium thiosulfate. Preliminary data on bisphosphonates, vitamin K and sodium thiosulfate are encouraging but larger studies on efficacy and outcomes are needed.

• Vascular calcification
• Coronary calcification
• Hemodialysis
• Dialysis
• Chronic kidney disease

Hemodialysis (HD) and hemodiafiltration clear only with a low efficiency the plasma from interleukin-6 and p-cresol, two protein-bound uremic toxins associated with high cardiovascular risk in end stage renal disease. HFR Supra is a double-chamber hemodiafiltration system in which the ultrafiltrate returns to the patient after its regeneration through a resin cartridge that binds hydrophobic and protein-bound solutes. In the present study, we evaluated whether the HFR cartridge can also bind total p-cresol and IL-6 and remove them from the ultrafiltrate.

We compared the levels of IL-6 and p-cresol in ultrafiltrate samples collected at the inlet (UF_in) and at the outlet (UF_out) of the cartridge at the start or at the end of a 240 min HFR session in 12 inflamed chronic HD patients. The pro-inflammatory activity of the ultrafiltrate samples was also determined by evaluating the changes that they induced in IL-6 mRNA expression and protein release in peripheral blood mononuclear cells from 12 healthy volunteers. IL-6 and p-cresol circulating levels were also assessed in peripheral plasma blood samples collected before and after HFR and, for comparison, a control HD.

p-Cresol and IL-6 were lower in UF_out than in UF_in both at the start and at the end of the HFR session, suggesting that they were retained by the cartridge. IL-6 mRNA expression and release were lower in PBMC incubated with UF_out collected at the end than with UF_in collected at the start of HFR, suggesting that passage through the cartridge reduced UF pro-inflammatory activity. Plasma total p-cresol decreased by about 53% after HFR, and 37% after HD. IL-6 circulating values were unmodified by either these dialysis procedures.

This study shows that the HFR-Supra cartridge retains total p-cresol and IL-6 in the ultrafiltrate and lowers plasma total p cresol but not IL-6 levels.

ClinicalTrials.gov NCT01865773