Roles of indoxyl sulfate in complications of chronic kidney disease / 中国临床药理学与治疗学

Chronic kidney disease is a global public health problem, and its occurrence and development are closely related to the exposure of uremic toxins in vivo. Indoxyl sulfate is one of protein-bound enterogenous uremic toxin, it significantly accumulates in patients with chronic kidney disease as renal function declines. Indoxyl sulfate not only promotes the progression of chronic kidney disease, but also induces pathological changes in other tissues and organs, causing complications in other organs related to chronic kidney disease. This article mainly reviews the effect of indoxyl sulfate on blood vessels, muscle, skeleton and brain and their mechanisms, and summarizes chronic kidney disease treatment by clearing indoxyl sulfate.

Piceatannol alleviates host inflammation in chronic kidney disease model mice through regulating gut microbiota / 药学学报

The purpose of this research is to study the effect of small molecule compound piceatannol (PIC) on host inflammation in adenine induced chronic kidney disease (CKD) mice, and then to explore its mechanism based on the regulation of gut microbiota. All procedures were approved by the Institutional Animal Care and Use Committee of the Nanjing University of Chinese Medicine. The level of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was detected by enzyme linked immunosorbent assay (ELISA); UPLC-TQ/MS technology was used to monitor the level of proinflammatory uremic toxin indoxyl sulfate (IS) and p-cresol sulfate (PCS); the expression of occludin was tested by Western blot; in vitro anaerobic culture of gut bacteria was used to produce indole; the abundance of gut microbiota was evaluated by 16S rDNA sequencing. The results showed that PIC had no effect on inflammatory infiltration in kidney tissue of CKD mice, but could decrease IL-6 level in blood and IL-6/TNF-α level in colon tissue. PIC did not improve intestinal occludin protein expression in CKD mice; while it could significantly reduce the levels of IS and PCS in blood and liver of CKD mice. Further mechanism studies showed that PIC could inhibit the synthesis of IS precursor indole in gut bacteria. Moreover, PIC could decrease the abundance of gut bacteria which producing uremic toxin, such as reducing the abundance of indole and p-cresol producing gut bacteria. In conclusion, PIC could regulate gut microbiota and inhibit the synthesis of uremic toxin precursor, thereafter reducing the accumulation of IS and PCS in vivo, ultimately relieving the inflammation of CKD mice.

Strategy to delay the progression of chronic kidney disease by targeting gut microbiota and uremic toxins metabolism pathway / 药学学报

Chronic kidney disease (CKD) is a serious chronic disease with high incidence, poor prognosis, and a variety of complications. Indoxyl-sulfate (IS) and p-cresol sulfate (PCS) are two typical gut-derived uremic toxins, which are produced by the co-metabolism of intestinal microbes and the host. With the progression of CKD, gut-derived uremic toxins such as IS and PCS accumulate in patients with CKD and thereafter accelerate the progression of CKD. Gut microbiota is closely related with CKD, and targeting gut microbiota to regulate gut-derived uremic toxins synthesis and metabolic pathways may be a promising strategy to delay the progression of CKD. In this paper, the relationship between gut microbiota, gut-derived uremic toxins, and CKD was analyzed, and the strategy to delay the progression of CKD by targeting gut microbiota and uremic toxins metabolism pathway was proposed.

Safety and effectiveness of hemoperfusion on the removal of uremic toxins in chronic kidney disease / 药学学报

The goal of the present study was to determine the effectiveness and safety of hemoperfusion (HP) in beagle dogs with chronic kidney disease (CKD). The experimental protocol was approved by the Institutional Animal Care and Use Committee of Tianjin Institute of Pharmaceutical Research New Drug Evaluation Research (IACUC2019071501). Twelve CKD model beagles were randomly divided into two groups: a low-frequency treatment group (n = 6) and a high-frequency treatment group (n = 6). The dogs in the high- and low-frequency groups received HP treatment every 3 days and once per week, respectively, for two treatments, with each session lasting 2 h. The test results showed that high-frequency HP treatment significantly decreased the accumulation of toxins in the CKD beagles. Hematology, coagulation function, electrolytes and liver function indicated that the HP treatment was safe. The body index effects were consistent between the low- and high-frequency treatment groups. Therefore, HP treatment once every 3 days was safe at the animal level. Multiple HP treatments every 3 days were more conducive than weekly treatments to the removal of uremic toxins with better prognosis and had no associated safety hazards.

Changes of working memory function and its risk factors in end-stage renal disease patients / 西安交通大学学报(医学版)

Objective: To explore the changes of working memory function and its risk factors in end-stage renal disease (ESRD) patients. Methods:We prospectively recruited 30 ESRD patients without dialysis and 23 healthy controls in The First Affiliated Hospital of Xi'an Jiaotong University from August 2016 to December 2017. The n-back working memory task with different loads was used to assess their working memory function; the general information of all the participants, arterial blood pressure and uremic toxins of the patients were collected to analyze the risk factors of working memory changes. Results: The reaction time of working memory with different loads was significantly longer than that in the healthy controls (P0.05). The correlation analysis showed that serum creatinine, blood urea nitrogen and parathyroid hormone levels were negatively correlated with the accuracy rate of working memory with different loads (P<0.05). Conclusion: The working memory function with different loads was impaired in ESRD patients. The accumulation of uremic toxins might be the risk factor for the working memory impairment in ESRD patients.

Uremic Toxins in Cognitive Impairment / 中国医学科学院学报

Patients with uremia can suffer from decreased renal function and endocrine and metabolism disorders,which can lead to the accumulation of toxins in the body.Accumulation of uremic toxins is a major cause of cognitive dysfunction in uremic patients.This article summarizes some of the cognitive dysfunction-related uremic toxins and their possible mechanisms.

Effect and mechanism of Huangkui capsuleon reduction of uremic toxin accumulation in an animal model of chronic kidney disease / 药学学报

Uremic toxins are harmful substances that accumulate in the body when the renal function declines in patients with chronic kidney disease (CKD). It is an important factor contributing to accelerated progression of CKD. There is no effective treatment for reducing uremic toxins. As an extensively used medicine for treatment of CKD in the clinic, Huangkui capsule is effective but the mechanism of its action remains unclear. This study investigated the effect of Huangkui on the accumulation of uremic toxins in CKD rats, with the discussion about its mechanism of action. UPLC-TQ/MS was used to detect the accumulation of uremic toxins in CKD rats after oral gavage with Huangkui. 16S rDNA sequencing technology was used to analyze the gut bacteria composition in rats. HPLC-FLD was used to detect the uremic toxins and their molecular precursors in feces. The effect and mechanism of Huangkui on the uremic toxin precursor in gut bacteria were studied by anaerobic culture system in vitro. All procedures were approved by the Institutional Animal Care and Use Committee of the Nanjing University of Chinese Medicine. The results showed that Huangkui (0.675 g·kg-1) could effectively inhibit the accumulation of uremic toxin indoxyl sulfate (IS) in CKD rats, with IS concentration in rat's plasma, liver and kidney decreased by 49.5%, 68.9% and 40.6%, respectively. Huangkui didn't affect the metabolic pathway of IS in host liver, didn't intervene the process of the IS precursor molecule indole conversion to IS. Instead, Huangkui significantly decreased the indole content in gut, with the indole in CKD rat's feces decreased by 46.4%, suggesting that the gut bacteria may be a target for intervene IS biosynthesis by Huangkui. Huangkui didn't affect the abundance of enterobacteriaceae bacteria (the main gut flora of indole synthesis) in CKD rats, suggesting that Huangkui didn't interfere with indole biosynthesis by directly affecting the abundance of indole synthesis related bacteria. Huangkui at 4 000, 400, 40, and 4 μg·mL-1 showed a dose-dependent inhibition of the indole production by gut bacteria in vitro. The bacteria tryptophan transport concentration decreased from 83.4 μmol·L-1 to 43.6 μmol·L-1 after co-incubated with Huangkui for 12 h, suggesting that Huangkui inhibited indole production of gut bacteria by interfering with tryptophan transportation. These results indicate that gut bacteria may be a potential target for alleviation of uremic toxin accumulation and for delaying CKD progression.

Bisphenol (A) uremic toxin to take into account in the Renal disease in Hemodialysis / Bisfenol (A) una toxina a tener en cuenta en el enfermo renal en hemodiálisis

Abstract Introduction: Most uremic toxins are by-products of protein metabolism by action of intestinal flora. The metabolism of aromatic amino acids originates phenolic type residues. The most studied is p-cresol that is associated with renal function and vascular damage. Bisphenol A (BPA) is an exogenous molecule with characteristics similar to these aromatic uremic toxins. BPA is an estrogenic endocrine disruptor, found in tin cans, plastic bottles, epoxy resins and in some dialyzers. This molecule accumulates in patients who have impaired renal function. Observational studies have shown that exposure of BPA is linked to renal and cardiovascular injury, among many others in humans, and in animal studies a causal link has been described. Kidneys with normal renal function rapidly excrete BPA, but insufficient excretion in patients with CKD results in accumulation of BPA in the body.

Resumen Muchas toxinas urémicas son originadas como consecuencia del catabolismo proteico por la flora intestinal. El metabolismo de aminoácidos aromáticos origina residuos de tipo fenólico. De estas toxinas, la más estudiada es el p-cresol, que se asocia a la función renal y daño vascular. El Bisfenol A (BPA) es una molécula exógena de características semejantes a estas toxinas urémicas aromáticas. El BPA es un disruptor endocrino estrogénico que se encuentra en latas de conserva, botellas de plástico, resinas epoxi y en algunos dializadores. Esta molécula se acumula en pacientes que tienen deteriorada la función renal. Estudios observacionales han demostrado que una exposición a BPA está vinculada, entre otras muchas, a lesión renal y cardiovascular en los seres humanos; en estudios en animales se ha descrito un vínculo causal. Los riñones con función renal normal excretan rápidamente BPA, pero una excreción insuficiente en pacientes con ERC da lugar a la acumulación del BPA en el organismo.

Sustained uremic toxin control improves renal and cardiovascular outcomes in patients with advanced renal dysfunction: post-hoc analysis of the Kremezin Study against renal disease progression in Korea

BACKGROUND: We investigated the long-term effect of AST-120, which has been proposed as a therapeutic option against renal disease progression, in patients with advanced chronic kidney disease (CKD). METHODS: We performed post-hoc analysis with a per-protocol group of the K-STAR study (Kremezin study against renal disease progression in Korea) that randomized participants into an AST-120 and a control arm. Patients in the AST-120 arm were given 6 g of AST-120 in three divided doses, and those in both arms received standard conventional treatment. RESULTS: The two arms did not differ significantly in the occurrence of composite primary outcomes (log-rank P = 0.41). For AST-120 patients with higher compliance, there were fewer composite primary outcomes: intermediate tertile hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.38 to 1.01, P = 0.05; highest tertile HR 0.436, 95% CI 0.25 to 0.76, P = 0.003. The estimated glomerular filtration rate level was more stable in the AST-120 arm, especially in diabetic patients. At one year, the AST-120-induced decrease in the serum indoxyl sulfate concentration inversely correlated with the occurrence of composite primary outcomes: second tertile HR 1.59, 95% CI 0.82 to 3.07, P = 0.17; third tertile HR 2.11, 95% CI 1.07 to 4.17, P = 0.031. Furthermore, AST-120 showed a protective effect against the major cardiovascular adverse events (HR 0.51, 95% CI 0.26 to 0.99, P = 0.046). CONCLUSION: Long-term use of AST-120 has potential for renal protection, especially in diabetic patients, as well as cardiovascular benefits. Reduction of the serum indoxyl sulfate level may be used to identify patients who would benefit from AST-120 administration.

Comparison of the effect of two blood purification technics in patients with chronic renal failure uremic / 中国医学装备

Objective: To evaluate the the effect of two blood purification in patients with chronic renal failure uremia. Methods: One hundred cases of patients from April 2012 to February 2014 in our hospital were chosen as the experimental object, and were divided into experimental group and control group, control group were treated with hemodiafiltration, and the experimental group were treated with high-flux hemodialysis,the serum medium and small molecule toxins and cognitive function improvement were compared. Results:The serum medium and small molecule toxins and cognitive function of two group were greatly improved, there were significant differences(t=4.113, t=0.430, t=1.038, t=0.346; P<0.05).The experimental group after treatment, serum phosphorus, parathyroid hormone was lower than the control group, the difference was statistically significant (t=-4.189, t=4.113;P<0.05). The experimental group PL and Amp were better than the patients in the control group, the difference was statistically significant (t=15.023, t=3.428; P<0.05). Conclusion: Two blood purification has good effect on treating patients with chronic renal failure uremia, but the improving effect of high flux hemodialysis scavenging effect on cysC, parathyroid hormone and serum phosphorus and cognitive function are better than that of hemodiafiltration.

Correlation between protein-bound uremic toxins and renal function in patients with chronic kidney disease stage 3-5 / 军事医学

Objective To investigate the serum concentrations of protein-bound uremic toxins of hippuric acid ( HA) , indoxyl sulfate ( IS ) , p-cresyl sulfate ( PCS ) and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid ( CMPF ) in patients with chronic kidney disease(CKD) 3-5 stages(CKD3-5) and to assess the correlation between renal function and pro-tein-bound uremic toxin concentrations in CKD3-5 patients.Methods Serum concentrations of HA, IS, PCS, and CMPF from 60 healthy volunteers and 112 CKD3 -5 patients were measured by liquid chromatography mass spectrometry/mass spectrometry ( HPLC-MS/MS ) .Correlation analysis was conducted between the levels of HA, IS, PCS, CMPF and the estimated glomerular filtration rate( eGFR) .Results Compared with healthy subjects, serum concentrations of these four solutes were significantly increased in CKD3-5 patients (all P0.05).Linear correlation analysis showed that HA, IS, PCS and CMPF were in significantly negative correlation with eGFR.The curve regression analysis showed that the curvilinear regression fitting equation was Y=-46.171lnX+209.464(R2 =0.601,P<0.01)for HA and eGFR, Y=-62.570 lnX+279.537(R2 =0.633,P<0.01)for IS and eGFR, Y=-84.297 lnX+383.172(R2 =0.529,P<0.01)for PCS and eGFR, and was Y=-7.648 lnX+53.546(R2 =0.172,P<0.01)for CMPF and eGFR .Conclusion The levels of the four types of protein-bound toxins in CKD3-5 patients increase significantly compared to healthy subjects.The serum levels of HA,IS and PCS are increased when the renal function decreases, but the level of CMPF changes little.Renal dysfunction can lead to significantly elevated levels of HA,IS and PCS in CKD3-5 patients, but has little effect on CMPF.

Isolation and identification of advanced oxidation protein products / 第三军医大学学报

Objective To isolate and identify advanced oxidation protein products from human serum albumin (AOPP-HSA), expecting to search for a method of preparing highly purified and bioactive AOPP-HSA. Methods AOPP-HSA crude products were prepared in vitro by exposing HSA to HOCl. AOPP-HSA was isolated by gel chromatography and ion-exchange HPLC. Its structural features and biological activities were characterized by UV and fluorescence spectrum, SDS-PAGE, and the experiment of TNF-? release from monocytes. Results The isolated protein was purified up to 99.4% and was dityrosine-containing protein cross-linking products with molecular weight of 700?10 3. It possessed the ability of triggering the considerable release of TNF-? from monocytes. Conclusion Highly purified and bioactive AOPP-HSA can be successfully prepared by above-mentioned two-step chromatography from AOPP-HSA crude products, which builds a basis for further study of AOPP.

Effects of uremic serum on TGF-?_1 of human renal tubular epithelial cells / 中国实用内科杂志

10 000 u,5 000~10 000u and 10 000 u group,and the gene expression was slightly increased in molecular weight 5 000～10 000 u group,but no significant difference of gene expression and protein secretion in 10 000 u uremic toxin,through promoting the gene expression and protein excretion of TGF-?_1 of renal tubular epithelial cells in patients with chronic renal failure.