Association between the uremic toxins indoxyl-sulfate and p-cresyl-sulfate with sarcopenia and malnutrition in elderly patients with advanced chronic kidney disease

Chronic kidney disease (CKD) is a major cause of death worldwide and is associated with a high risk for cardiovascular and all-cause mortality. In CKD, endothelial dysfunction occurs and uremic toxins accumulate in the blood. miR-126 is a regulator of endothelial dysfunction and its blood level is decreased in CKD patients. In order to obtain a better understanding of the physiopathology of the disease, we correlated the levels of miR-126 with several markers of endothelial dysfunction, as well as the representative uremic toxins, in a large cohort of CKD patients at all stages of the disease. Using a univariate analysis, we found a correlation between eGFR and most markers of endothelial dysfunction markers evaluated in this study. An association of miR-126 with all the evaluated uremic toxins was also found, while uremic toxins were not associated with the internal control, specifically cel-miR-39. The correlation between the expression of endothelial dysfunction biomarker Syndecan-1, free indoxyl sulfate, and total p-cresyl glucuronide on one side, and miR-126 on the other side was confirmed using multivariate analysis. As CKD is associated with reduced endothelial glycocalyx (eGC), our results justify further evaluation of the role of correlated parameters in the pathophysiology of CKD.

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FO028FRIED’S FRAILTY SCALE IDENTIFIES THOSE ELDERLY PATIENTS WITH ADVANCED CHRONIC KIDNEY DISEASE THAT MAY BENEFIT FROM A THOROUGH GERIATRIC EVALUATION

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfy104.fo028 ◽

2018 ◽

Vol 33 (suppl_1) ◽

pp. i29-i29

Author(s):

Lara Caldiroli ◽

Carlotta Vezza ◽

Piergiorgio Messa ◽

Matteo Cesari ◽

Simone Vettoretti

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Elderly Patients ◽

Advanced Chronic Kidney Disease ◽

Geriatric Evaluation

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Impacts of Indoxyl Sulfate and p-Cresol Sulfate on Chronic Kidney Disease and Mitigating Effects of AST-120

Toxins ◽

10.3390/toxins10090367 ◽

2018 ◽

Vol 10 (9) ◽

pp. 367 ◽

Cited By ~ 38

Author(s):

Wen-Chih Liu ◽

Yasuhiko Tomino ◽

Kuo-Cheng Lu

Keyword(s):

Oxidative Stress ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Large Scale ◽

Interstitial Fibrosis ◽

Uremic Toxins ◽

Indoxyl Sulfate ◽

Renal Diseases ◽

Glomerular Sclerosis ◽

Inflammatory Reactions

Uremic toxins, such as indoxyl sulfate (IS) and p-cresol, or p-cresyl sulfate (PCS), are markedly accumulated in the organs of chronic kidney disease (CKD) patients. These toxins can induce inflammatory reactions and enhance oxidative stress, prompting glomerular sclerosis and interstitial fibrosis, to aggravate the decline of renal function. Consequently, uremic toxins play an important role in the worsening of renal and cardiovascular functions. Furthermore, they destroy the quantity and quality of bone. Oral sorbent AST-120 reduces serum levels of uremic toxins in CKD patients by adsorbing the precursors of IS and PCS generated by amino acid metabolism in the intestine. Accordingly, AST-120 decreases the serum IS levels and reduces the production of reactive oxygen species by endothelial cells, to impede the subsequent oxidative stress. This slows the progression of cardiovascular and renal diseases and improves bone metabolism in CKD patients. Although large-scale studies showed no obvious benefits from adding AST-120 to the standard therapy for CKD patients, subsequent sporadic studies may support its use. This article summarizes the mechanisms of the uremic toxins, IS, and PCS, and discusses the multiple effects of AST-120 in CKD patients.

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Indoxyl Sulfate Predicts Cardiovascular Disease and Renal Function Deterioration in Advanced Chronic Kidney Disease

Archives of Medical Research ◽

10.1016/j.arcmed.2012.08.002 ◽

2012 ◽

Vol 43 (6) ◽

pp. 451-456 ◽

Cited By ~ 78

Author(s):

Cheng-Jui Lin ◽

Hsuan-Liang Liu ◽

Chi-Feng Pan ◽

Chih-Kuang Chuang ◽

Thanasekaran Jayakumar ◽

...

Keyword(s):

Cardiovascular Disease ◽

Chronic Kidney Disease ◽

Renal Function ◽

Kidney Disease ◽

Indoxyl Sulfate ◽

Advanced Chronic Kidney Disease ◽

Renal Function Deterioration

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Canagliflozin reduces plasma uremic toxins and alters the intestinal microbiota composition in a chronic kidney disease mouse model

AJP Renal Physiology ◽

10.1152/ajprenal.00314.2017 ◽

2018 ◽

Vol 315 (4) ◽

pp. F824-F833 ◽

Cited By ~ 20

Author(s):

Eikan Mishima ◽

Shinji Fukuda ◽

Yoshitomi Kanemitsu ◽

Daisuke Saigusa ◽

Chikahisa Mukawa ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Renal Failure ◽

Kidney Disease ◽

Therapeutic Option ◽

Short Chain Fatty Acids ◽

Inhibitory Effect ◽

Uremic Toxins ◽

Indoxyl Sulfate ◽

Vehicle Group ◽

Microbiota Composition

Accumulation of uremic toxins, which exert deleterious effects in chronic kidney disease, is influenced by the intestinal environment; the microbiota contributes to the production of representative uremic toxins, including p-cresyl sulfate and indoxyl sulfate. Canagliflozin is a sodium-glucose cotransporter (SGLT) 2 inhibitor, and it also exerts a modest inhibitory effect on SGLT1. The inhibition of intestinal SGLT1 can influence the gastrointestinal environment. We examined the effect of canagliflozin on the accumulation of uremic toxins in chronic kidney disease using adenine-induced renal failure mice. Two-week canagliflozin (10 mg/kg po) treatment did not influence the impaired renal function; however, it significantly reduced the plasma levels of p-cresyl sulfate and indoxyl sulfate in renal failure mice (a 75% and 26% reduction, respectively, compared with the vehicle group). Additionally, canagliflozin significantly increased cecal short-chain fatty acids in the mice, suggesting the promotion of bacterial carbohydrate fermentation in the intestine. Analysis of the cecal microbiota showed that canagliflozin significantly altered microbiota composition in the renal failure mice. These results indicate that canagliflozin exerts intestinal effects that reduce the accumulation of uremic toxins including p-cresyl sulfate. Reduction of accumulated uremic toxins by canagliflozin could provide a potential therapeutic option in chronic kidney disease.

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The association of beta-blocker use with mortality in elderly patients with congestive heart failure and advanced chronic kidney disease

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfz167 ◽

2019 ◽

Vol 35 (5) ◽

pp. 782-789 ◽

Cited By ~ 6

Author(s):

Amber O Molnar ◽

William Petrcich ◽

Matthew A Weir ◽

Amit X Garg ◽

Michael Walsh ◽

...

Keyword(s):

Heart Failure ◽

Chronic Kidney Disease ◽

Congestive Heart Failure ◽

Kidney Disease ◽

Elderly Patients ◽

Randomized Trials ◽

Advanced Chronic Kidney Disease ◽

All Cause Mortality ◽

Β Blocker ◽

Β Blockers

Abstract Background Whether the survival benefit of β-blockers in congestive heart failure (CHF) from randomized trials extends to patients with advanced chronic kidney disease (CKD) [estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 but not receiving dialysis] is uncertain. Methods This was a retrospective cohort study using administrative datasets. Older adults from Ontario, Canada, with incident CHF (median age 79 years) from April 2002 to March 2014 were included. We matched new users of β-blockers to nonusers on age, sex, eGFR categories (>60, 30–60, <30), CHF diagnosis date and a high-dimensional propensity score. Using Cox proportional hazards models, we examined the association of β-blocker use versus nonuse with all-cause mortality. Results We matched 5862 incident β-blocker users (eGFR >60, n = 3136; eGFR 30–60, n = 2368; eGFR <30, n = 358). There were 2361 mortality events during follow-up. β-Blocker use was associated with reduced all-cause mortality [adjusted hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.54–0.64]. This result was consistent across all eGFR categories (>60: adjusted HR 0.55, 95% CI 0.49–0.62; 30–60: adjusted HR 0.63, 95% CI 0.55–0.71; <30: adjusted HR 0.55, 95% CI 0.41–0.73; interaction term, P = 0.30). The results were consistent in an intention-to-treat analysis and with β-blocker use treated as a time-varying exposure. Conclusions β-Blocker use is associated with reduced all-cause mortality in elderly patients with CHF and CKD, including those with an eGFR <30. Randomized trials that examine β-blockers in patients with CHF and advanced CKD are needed.

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