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

Protein-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.

A new horizon for the old antibacterial drug clofoctol.

The synthetic antibacterial drug clofoctol (CFT) has long been used to treat respiratory tract infections in Europe. In recent years, the drug was found to target two biologically important proteins, the Cdc7/Dbf4 protein kinase complex and the mRNA-binding protein cold shock domain containing E1 (CSDE1), also known as upstream-of-N-Ras protein (UNR). These interactions are at the origin of the antitumor activity of CFT, recently evidenced in prostate cancer and neuroglioma. Drug-protein binding models provide a structural basis to guide the design of more potent anticancer compounds. A renewed interest in CFT can be anticipated for the treatment of cancers, and possibly Coronavirus 2019 (COVID-19).

The specific impact of uremic toxins upon cognitive domains: a review / O impacto específico de toxinas urêmicas em domínios cognitivos: uma revisão

ABSTRACT One of the mechanisms proposed for chronic kidney disease (CKD)-related cognitive impairment is the accumulation of uremic toxins due to the deterioration of the renal clearance function. Cognition can be categorized into five major domains according to its information processing functions: memory, attention, language, visual-spatial, and executive. We performed a review using the terms 'uric acid', 'indoxyl sulfate', 'p-cresyl sulfate', 'homocysteine', 'interleukins' and 'parathyroid hormone'. These are the compounds that were found to be strongly associated with cognitive impairment in CKD in the literature. The 26 selected articles point towards an association between higher levels of uric acid, homocysteine, and interleukin 6 with lower cognitive performance in executive, attentional, and memory domains. We also reviewed the hemodialysis effects on cognition. Hemodialysis seems to contribute to an amelioration of CKD-related encephalopathic dysfunction, although this improvement occurs more in some cognitive domains than in others.

RESUMO Um dos mecanismos propostos para explicar o comprometimento cognitivo relacionado à doença renal crônica (DRC) é o acúmulo de toxinas urêmicas devido à deterioração da função de depuração renal. A cognição pode ser categorizada em cinco domínios principais de acordo com suas funções de processamento de informações: memória, atenção, linguagem, visual-espacial e executiva. Realizamos uma revisão usando os termos "ácido úrico", "indoxil sulfato", "p-cresil sulfato", "homocisteína", "interleucinas" e "paratormônio". Estes são os compostos que se mostraram fortemente associados ao comprometimento cognitivo na DRC na literatura. Os 26 artigos selecionados apontam para uma associação entre níveis mais elevados de ácido úrico, homocisteína e interleucina-6 com menor desempenho cognitivo nos domínios executivo, atenção e de memória. Também revisamos os efeitos da hemodiálise na cognição. A hemodiálise parece contribuir para uma melhoria da disfunção encefalopática relacionada à DRC, embora essa melhora ocorra mais em alguns domínios cognitivos do que em outros.

TUDCA-Treated Mesenchymal Stem Cells Protect against ER Stress in the Hippocampus of a Murine Chronic Kidney Disease Model.

Chronic kidney disease (CKD) leads to the loss of kidney function, as well as the dysfunction of several other organs due to the release of uremic toxins into the system. In a murine CKD model, reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress are increased in the hippocampus. Mesenchymal stem cells (MSCs) are one of the candidates for cell-based therapy for CKD; however severe pathophysiological conditions can decrease their therapeutic potential. To address these issues, we established tauroursodeoxycholic acid (TUDCA)-treated MSCs using MSCs isolated from patients with CKD (CKD-hMSCs) and assessed the survival and ROS generation of neural cell line SH-SY5Y cells by co-culturing with TUDCA-treated CKD-hMSCs. In the presence of the uremic toxin P-cresol, the death of SH-SY5Y cells was induced by ROS-mediated ER stress. Co-culture with TUDCA-treated CKD-hMSCs increased anti-oxidant enzyme activities in SH-SY5Y cells through the upregulation of the cellular prion protein (PrPC) expression. Upregulated PrPC expression in SH-SY5Y cells protected against CKD-mediated ER stress and apoptosis. In an adenine-induced murine CKD model, injection with TUDCA-treated CKD-hMSCs suppressed ROS generation and ER stress in the hippocampus. These results indicate that TUDCA-treated CKD-hMSCs prevent the CKD-mediated cell death of SH-SY5Y cells by inhibiting ER stress. Our study suggests that treatment with TUDCA could be a powerful strategy for developing autologous MSC-based therapeutics for patients with CKD, and that PrPC might be a pivotal target for protecting neural cells from CKD-mediated ER stress.

The specific impact of uremic toxins upon cognitive domains: a review.

One of the mechanisms proposed for chronic kidney disease (CKD)-related cognitive impairment is the accumulation of uremic toxins due to the deterioration of the renal clearance function. Cognition can be categorized into five major domains according to its information processing functions: memory, attention, language, visual-spatial, and executive. We performed a review using the terms 'uric acid', 'indoxyl sulfate', 'p-cresyl sulfate', 'homocysteine', 'interleukins' and 'parathyroid hormone'. These are the compounds that were found to be strongly associated with cognitive impairment in CKD in the literature. The 26 selected articles point towards an association between higher levels of uric acid, homocysteine, and interleukin 6 with lower cognitive performance in executive, attentional, and memory domains. We also reviewed the hemodialysis effects on cognition. Hemodialysis seems to contribute to an amelioration of CKD-related encephalopathic dysfunction, although this improvement occurs more in some cognitive domains than in others.

Pioglitazone Protects Mesenchymal Stem Cells against P-Cresol-Induced Mitochondrial Dysfunction via Up-Regulation of PINK-1.

Mesenchymal stem cells (MSC) could be a candidate for cell-based therapy in chronic kidney disease (CKD); however, the uremic toxin in patients with CKD restricts the therapeutic efficacy of MSCs. To address this problem, we explored the effect of pioglitazone as a measure against exposure to the uremic toxin P-cresol (PC) in MSCs. Under PC exposure conditions, apoptosis of MSCs was induced, as well as PC-induced dysfunction of mitochondria by augmentation of mitofusion, reduction of mitophagy, and inactivation of mitochondrial complexes I and IV. Treatment of MSCs with pioglitazone significantly inhibited PC-induced apoptosis. Pioglitazone also prevented PC-induced mitofusion and increased mitophagy against PC exposure through up-regulation of phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK-1). Furthermore, pioglitazone protected against PC-induced mitochondrial dysfunction by increasing the cytochrome c oxidase subunit 4 (COX4) level and activating complexes I and IV, resulting in enhancement of proliferation. In particular, activation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) regulated the pioglitazone-mediated up-regulation of PINK-1. These results indicate that pioglitazone protects MSCs against PC-induced accumulated mitochondrial dysfunction via the NF-κB⁻PINK-1 axis under P-cresol exposure conditions. Our study suggests that pioglitazone-treated MSCs could be a candidate for MSC-based therapy in patients with CKD.

Residents' Self-Reported Health Effects and Annoyance in Relation to Air Pollution Exposure in an Industrial Area in Eastern-Estonia.

Eastern Estonia has large oil shale mines and industrial facilities mainly focused on electricity generation from oil shale and shale oil extraction, which produce high air pollution emissions. The "Study of the health impact of the oil shale sector-SOHOS" was aimed at identifying the impacts on residents' health and annoyance due to the industrial processing. First, a population-wide survey about health effects and annoyance was carried out. Second, the total and oil shale sectors' emitted concentrations of benzene, phenol, and PM2.5 were modelled. Third, the differences between groups were tested and relationships between health effects and environmental pollution studied using multiple regression analysis. Compared to the control groups from non-industrial areas in Tartu or Lääne-Viru, residents of Ida-Viru more frequently (p < 0.05) reported wheezing, chest tightness, shortness of breath, asthma attacks, a long-term cough, hypertension, heart diseases, myocardial infarction, stroke, and diabetes. All health effects except asthma were reported more frequently among non-Estonians. People living in regions with higher levels of PM2.5, had significantly higher odds (p < 0.05) of experiencing chest tightness (OR = 1.13, 95% CI 1.02-1.26), shortness of breath (1.16, 1.03-1.31) or an asthma attack (1.22, 1.04-1.42) during the previous year. People living in regions with higher levels of benzene had higher odds of experiencing myocardial infarction (1.98, 1.11-3.53) and with higher levels of phenol chest tightness (1.44, 1.03-2.00), long-term cough (1.48, 1.06-2.07) and myocardial infarction (2.17, 1.23-3.83). The prevalence of adverse health effects was also higher among those who had been working in the oil shale sector. Next to direct health effects, up to a quarter of the residents of Ida-Viru County were highly annoyed about air pollution. Perceived health risk from air pollution increased the odds of being annoyed. Annoyed people in Ida-Viru had significantly higher odds of experiencing respiratory symptoms during the last 12 months, e.g., wheezing (2.30, 1.31-4.04), chest tightness (2.88, 1.91-4.33 or attack of coughing (1.99, 1.34-2.95).

p-Cresyl Sulfate.

If chronic kidney disease (CKD) is associated with an impairment of kidney function, several uremic solutes are retained. Some of these exert toxic effects, which are called uremic toxins. p-Cresyl sulfate (pCS) is a prototype protein-bound uremic toxin to which many biological and biochemical (toxic) effects have been attributed. In addition, increased levels of pCS have been associated with worsening outcomes in CKD patients. pCS finds its origin in the intestine where gut bacteria metabolize aromatic amino acids, such as tyrosine and phenylalanine, leading to phenolic end products, of which pCS is one of the components. In this review we summarize the biological effects of pCS and its metabolic origin in the intestine. It appears that, according to in vitro studies, the intestinal bacteria generating phenolic compounds mainly belong to the families Bacteroidaceae, Bifidobacteriaceae, Clostridiaceae, Enterobacteriaceae, Enterococcaceae, Eubacteriaceae, Fusobacteriaceae, Lachnospiraceae, Lactobacillaceae, Porphyromonadaceae, Staphylococcaceae, Ruminococcaceae, and Veillonellaceae. Since pCS remains difficult to remove by dialysis, the gut microbiota could be a future target to decrease pCS levels and its toxicity, even at earlier stages of CKD, aiming at slowing down the progression of the disease and decreasing the cardiovascular burden.

p-Cresyl sulfate promotes the formation of atherosclerotic lesions and induces plaque instability by targeting vascular smooth muscle cells.

Coronary atherosclerosis is a major complication of chronic kidney disease. This condition contributes to the increased mortality in dialysis patients. p-Cresyl sulfate (PCS) is a prototype of protein-bound uremic toxins that cannot be efficiently removed through routine dialysis procedures. In the present study, ApoE(-/-) mice that underwent 5/6 nephrectomy were randomly divided into two groups, namely, vehicle-treated group (n = 20) and PCS-treated group (n = 20). Mice were sacrificed for en face and immunohistological analyses after 8 or 24 weeks of high-fat diet. Rat aortic vascular smooth muscle cells (VSMCs) were treated with phosphate buffer solution or 500 µmol/L PCS for in vitro evaluation. PCS-treated mice were observed to suffer increased atherosclerotic lesions after eight weeks of PCS administration. Moreover, 24 weeks of PCS administration also markedly increased the vulnerability index of aortic plaques. PCS was also observed to facilitate the migration and proliferation of VSMCs during the progression of the disease. Moreover, PCS disturbed the balance between matrix metalloproteinases and tissue inhibitor of metalloproteinases within the plaques. Thus, PCS played a vital role in promoting atherogenesis and disturbing the stability of formed plaques probably by targeting VSMCs.

Deleterious Effect of p-Cresol on Human Colonic Epithelial Cells Prevented by Proanthocyanidin-Containing Polyphenol Extracts from Fruits and Proanthocyanidin Bacterial Metabolites.

The protective effect of proanthocyanidin-containing polyphenol extracts from apples, avocados, cranberries, grapes, or proanthocyanidin microbial metabolites was evaluated in colonic epithelial cells exposed to p-cresol, a deleterious compound produced by the colonic microbiota from l-tyrosine. In HT29 Glc(-/+) cells, p-cresol significantly increased LDH leakage and decreased ATP contents, whereas in Caco-2 cell monolayers, it significantly decreased the transepithelial electrical resistance and increased the paracellular transport of FITC-dextran. The alterations induced by p-cresol in HT29 Glc(-/+) cells were prevented by the extracts from cranberries and avocados, whereas they became worse by extracts from apples and grapes. The proanthocyanidin bacterial metabolites decreased LDH leakage, ameliorating cell viability without improving intracellular ATP. All of the polyphenol extracts and proanthocyanidin bacterial metabolites prevented the p-cresol-induced alterations of barrier function. These results suggest that proanthocyanidin-containing polyphenol extracts and proanthocyanidin metabolites likely contribute to the protection of the colonic mucosa against the deleterious effects of p-cresol.

Single uroflow study as a tool in predicting the possibility of abnormal voiding symptoms after the administration of antimuscarinic agents in treating overactive bladder syndrome.

PURPOSE OF STUDY: The aim of this study was to evaluate the efficacy of uroflowmetry in predicting the possibility of abnormal voiding symptoms following antimuscarinic treatment for overactive bladder syndrome (OAB) in Taiwanese women. MATERIALS AND METHODS: A retrospective study was conducted on women with OAB. Forty-five women with abnormal voiding patterns shown by urodynamic study comprised the main group and 38 women with normal voiding patterns comprised the control group. All patients were prescribed two mg tolterodine once daily for one week. Follow-up on complaints of abnormal voiding symptoms was done one week later. RESULTS: One woman in control group and 12 women in main group complained of abnormal voiding symptoms. There was a significant difference in the occurrence of abnormal voiding symptoms after antimuscarinic administration between main study group and control group (26.7 % vs 2.6 %, p = 0.02). CONCLUSIOn: Uroflowmetry is a non-invasive and simple tool to predict the occurrence of abnormal voiding symptoms after antimuscarinic use.

Prominent complaint: a guide to medical therapy of overactive bladder syndrome in older women.

To evaluate Overactive bladder (OAB) with detrusor overactivity (DOA) following oxybutynin or tolterodine treatment in recommended doses at a four-week course. A total of 100 Iranian women 45 years or older with urgency that also showed idiopathic detrusor overactivity (IDO) in the filling phase of their cystometry were included in the current study. In this double-blinded trial two parallel groups were randomized by using two kinds of the antimuscarinic drugs for a four- week course [oxybutinin 5mg, t.d.s. or Tolterodin 2mg, b.i.d.] in the same  packages. Data were collected from three-day frequency volume chart (FVC) one month before and after the treatment course. The effectiveness of each drug was compared using the paired, samples t-test. Patients' improvement regarding urinary urgency, frequency and urge incontinence after treatment in both groups was seen, but mean improvements in the terms of urgency and urge incontinence were larger in patients who were treated by oxybutynin. Night-time frequency was shown to be improved by a significantly larger score by tolterodine. Discontinuation of treatment due to adverse events had no significant difference in two groups. Four-week treatment with oxybutynin was better than tolterodine IR in improving urgency and urge incontinence, but there were not statistically significant difference between them. In planning a course of treatment especially in the elderly, the difference in the group of symptoms that reduce patients' quality of life should be considered. Physicians should consider the patient's prominent symptom in selection of anti-muscarinic drugs for the treatment of overactive bladder syndrome especially in elderly patients.

Influence of antimuscarinic therapy on cognitive functions and quality of life in geriatric patients treated for overactive bladder.

OBJECTIVES: Incidences of overactive bladder (OAB) and cognitive dysfunction increase with aging. Treatment of OAB with antimuscarinic agents may result in cognitive decline, especially in patients with Alzheimer's disease (AD). The aim of this study is to evaluate the effect of antimuscarinic treatment on cognitive functions, depression, and quality of life (QOL) of patients with OAB. METHODS: This non-interventional prospective observational study was conducted in a geriatric medicine outpatient clinic. Overall, 168 OAB patients were enrolled. Patients were followed up in five groups: oxybutynin, darifenacin, tolterodine, trospium, and control groups. Follow-up visits were done at second, third, and sixth months. Comprehensive geriatric assessment, cognitive and mood assessment, QOL scales (IIQ-7, UDI-6) were performed. RESULTS: Mean age of the patients was 73.5 ± 6.1. Of the 168 patients, 92.3% were female, 83.3% benefited from the treatment, and 37.1% discontinued the medication. Discontinuation rate and frequency of side effects were more frequent in the oxybutynin group. Mini Mental State Examination scores did not decline after treatment, even in AD patients. Geriatric Depression Scale scores, Activities of Daily Living scores, and QOL scores significantly improved after treatment. CONCLUSION: Antimuscarinic agents are effective in OAB treatment. They have a positive impact on daily life activities, depression, and QOL indices. Furthermore, they do not have a negative effect on cognitive function in older adults with or without AD.

Tolterodine extended release in the treatment of male OAB/storage LUTS: a systematic review.

BACKGROUND: Overactive bladder (OAB)/ storage lower urinary tract symptoms (LUTS) have a high prevalence affecting up to 90% of men over 80 years. The role of sufficient therapies appears crucial. In the present review, we analyzed the mechanism of action of tolterodine extended-release (ER) with the aim to clarify its efficacy and safety profile, as compared to other active treatments of OAB/storage LUTS. METHODS: A wide Medline search was performed including the combination of following words: "LUTS", "BPH", "OAB", "antimuscarinic", "tolterodine", "tolterodine ER". IPSS, IPSS storage sub-score and IPSS QoL (International Prostate Symptom Score) were the validated efficacy outcomes. In addition, the numbers of urgency episodes/24 h, urgency incontinence episodes/24 h, incontinence episodes/24 h and pad use were considered. We also evaluated the most common adverse events (AEs) reported for tolterodine ER. RESULTS: Of 128 retrieved articles, 109 were excluded. The efficacy and tolerability of tolterodine ER Vs. tolterodine IR have been evaluated in a multicenter, double-blind, randomized placebo controlled study in 1529 patients with OAB. A 71% mean reduction in urgency incontinence episodes was found in the tolterodine ER group compared to a 60% reduction in the tolterodine IR (p < 0.05). Few studies evaluated the clinical efficacy of α-blocker/tolterodine combination therapy. In patients with large prostates (prostate volume >29 cc) only the combination therapy significantly reduced 24-h voiding frequency (2.8 vs. 1.7 with tamsulosin, 1.4 with tolterodine, or 1.6 with placebo). A recent meta-analysis evaluating tolterodine in comparison with other antimuscarinic drugs demonstrated that tolterodine ER was significantly more effective than placebo in reducing micturition/24 h, urinary leakage episodes/24 h, urgency episodes/24 h, and urgency incontinence episodes/24 h. With regard to adverse events, tolterodine ER was associated with a good adverse event profile resulting in the third most favorable antimuscarinic. Antimuscarinic drugs are the mainstay of pharmacological therapy for OAB / storage LUTS; several studies have demonstrated that tolterodine ER is an effective and well tolerated formulation of this class of treatment. CONCLUSION: Tolterodine ER resulted effective in reducing frequency urgency and nocturia and urinary leakage in male patients with OAB/storage LUTS. Dry mouth and constipation are the most frequently reported adverse events.

Are we shortchanging frail older people when it comes to the pharmacological treatment of urgency urinary incontinence?

Overactive bladder and urgency incontinence are common and distressing conditions in older people, for which the first-line pharmacological treatment is a bladder antimuscarinic agent. Of these, oxybutynin is often recommended in guidelines, but is associated with a higher incidence of adverse drug effects, and in particular has been suggested to have deleterious cognitive effects. Despite this, guidelines often suggest oxybutynin as first-line treatment, and insurance based healthcare systems often require oxybutynin to be used as a first-line therapy and fail before reimbursement for the cost of newer anticholinergics is authorised. We reviewed the literature of bladder antimuscarinics in older adults, using the headings overactive bladder, urinary frequency, urgency, urge, oxybutynin, antimuscarinic, older, older people, and frail. In general, oxybutynin had a similar efficacy to other anticholinergic drugs, but a higher incidence of adverse drug events, in particular significant yet unnoticed cognitive impairment. We conclude that oxybutynin should not be used in frail older people.

[Treatment of overactive bladder in older women increased doses of antimuscarinic drugs safe and effective alternative to existing methods].

The study included 95 female patients of 65 to 74 years (average age 67,1 years), who previously (more than 6 months before this study) took a course of monotherapy with hydrochloride trospium in higher dosages with unstable or weak effect. In this study, all patients were divided into three groups and were treated with two antimuscarinic drugs. The majority of older women suffering from OAB and treatment-resistant taking one antimuscarinic drug in high doses showed a significant positive progress in a state by adding a second antimuscarinic agent. The received side effects do not exceed thereof in comparison with treatment with a single drug.