Effect of CKD-MBD therapies on the gastrointestinal expression of phosphate transporters

Background: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is prevalent and encompasses biochemical abnormalities, bone alterations, and vascular calcifications. CKD-MBD treatments include phosphate binders and calcimimetics that effectively lower phosphorus and PTH, respectively, but the impact of these treatments on phosphate transporters in the gastrointestinal tract is still unknown. NaPi2B is considered the primary intestinal phosphate transporter. However, NaPi2B inhibition shows limited effectiveness, thus the importance of PIT1 and PIT2 requires further investigation. Methods: We tested the effects phosphate binders (ferric citrate (FC) and calcium gluconate (Ca)) and the calcimimetic KP2326 (KP) in (Cy/+ male rat; CKD) and untreated normal littermates (NL). Treatments lasted 10 weeks until euthanasia at 28 weeks (moderate-to-advanced CKD), where we collected mucosa samples from duodenum, jejunum, and ileum. Blood was collected for biochemistry measurements. Total RNA was isolated, and qPCR performed to assess phosphate transporters expression (NaPi2B, PIT1, PIT2) normalized to b-actin. Results were analyzed via 2-way ANOVA. Results: As expected, CKD had abnormal plasma concentrations of phosphorus, PTH, and FGF23. FC and KP effectively lowered phosphorus. KP and Ca lowered PTH, but Ca increased FGF23. NaPi2B was expressed in the duodenum and jejunum but not in the ileum, and its expression was upregulated with FC compared to NL. PIT1 was expressed in all segments, but the expression was the highest in the ileum, while PIT2 was constitutively expressed in all segments. Ca led to higher PIT1 and PIT2 expression in the duodenum and jejunum compared to NL, CKD, or KP. KP led to higher expression of PIT1 in the ileum compared to CKD, FC, and Ca. Conclusions: CKD-MBD therapies differentially impacted biochemistries and phosphate transporters expression. The effect of Ca on gastrointestinal expression of PIT1 and PIT2 may explain the higher plasma phosphorus and should be further explored.

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Effects of the Use of Non-Calcium Phosphate Binders in the Control and Outcome of Vascular Calcifications: A Review of Clinical Trials on CKD Patients

International Journal of Nephrology ◽

10.4061/2011/758450 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Piergiorgio Bolasco

Keyword(s):

Calcium Phosphate ◽

Mortality Rates ◽

Morbidity And Mortality ◽

Phosphate Binders ◽

Vascular Calcifications ◽

Mineral Bone Disorder ◽

Bone Disorder ◽

Advanced Stages ◽

The Impact ◽

Specific Contribution

Vascular calcifications produce a high impact on morbidity and mortality rates in patients affected by chronic kidney disease and mineral bone disorder (CKD-MBD). Effects are manifested from the more advanced stages of CKD (stages 3-4), particularly in patients undergoing dialysis (CKD5D). In recent years, a large number of therapeutic options have been successfully used in the treatment of secondary hyperparathyroidism (SHPT), despite eliciting less marked effects on nonbone calcifications associated with CKD-MBD. In addition to the use of Vitamin D and analogues, more recently treatment with calcimimetic drugs has also been undertaken. The present paper aims to analyze comparative and efficacy studies undertaken to assess particularly the impact on morbidity and mortality rates of non-calcium phosphate binders. Moreover, the mechanism of action underlying the depositing of calcium and phosphate along blood vessel walls, irrespective of the specific contribution provided in reducing the typical phosphate levels observed in CKD largely at more advanced stages of the disease, will be investigated. The aim of this paper therefore is to evaluate which phosphate binders are characterised by the above action and the mechanisms through which these are manifested.

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Phosphate, Microbiota and CKD

Nutrients ◽

10.3390/nu13041273 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1273

Author(s):

Chiara Favero ◽

Sol Carriazo ◽

Leticia Cuarental ◽

Raul Fernandez-Prado ◽

Elena Gomá-Garcés ◽

...

Keyword(s):

Gut Microbiota ◽

Current Knowledge ◽

Adverse Outcomes ◽

Phosphate Binders ◽

Uremic Toxin ◽

Mineral And Bone Disorder ◽

Dietary Phosphate ◽

The Impact ◽

The Relationship

Phosphate is a key uremic toxin associated with adverse outcomes. As chronic kidney disease (CKD) progresses, the kidney capacity to excrete excess dietary phosphate decreases, triggering compensatory endocrine responses that drive CKD-mineral and bone disorder (CKD-MBD). Eventually, hyperphosphatemia develops, and low phosphate diet and phosphate binders are prescribed. Recent data have identified a potential role of the gut microbiota in mineral bone disorders. Thus, parathyroid hormone (PTH) only caused bone loss in mice whose microbiota was enriched in the Th17 cell-inducing taxa segmented filamentous bacteria. Furthermore, the microbiota was required for PTH to stimulate bone formation and increase bone mass, and this was dependent on bacterial production of the short-chain fatty acid butyrate. We review current knowledge on the relationship between phosphate, microbiota and CKD-MBD. Topics include microbial bioactive compounds of special interest in CKD, the impact of dietary phosphate and phosphate binders on the gut microbiota, the modulation of CKD-MBD by the microbiota and the potential therapeutic use of microbiota to treat CKD-MBD through the clinical translation of concepts from other fields of science such as the optimization of phosphorus utilization and the use of phosphate-accumulating organisms.

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Vitamin D and Blood Parameters

Biomolecules ◽

10.3390/biom11071017 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1017

Author(s):

Thomas Müller ◽

Lutz Lohse ◽

Andreas Blodau ◽

Katja Frommholz

Keyword(s):

Vitamin D ◽

Mean Corpuscular Volume ◽

Plasma Concentrations ◽

Blood Parameters ◽

Vitamin D Supplementation ◽

Mean Corpuscular Hemoglobin ◽

Corpuscular Volume ◽

Corpuscular Haemoglobin ◽

Mean Corpuscular Haemoglobin ◽

The Impact

Background: Vitamin D has a steroid- and an anabolic-resembling chemical structure. Vitamin D is essential for many processes in the human body after hydroxylation. Aims of the Study: To investigate the impact of 25-hydroxy-vitamin D plasma concentrations on the blood parameters number of erythrocytes, hematocrit, mean corpuscular hemoglobin and mean corpuscular volume. Methods: Serial assessments were done in 290 patients with multiple sclerosis and repeated after a mean interval of 245 days. A recommendation for vitamin D supplementation was given in case of a concentration lower than 20 ng/mL combined with a prescription of a formulation containing vitamin D but not vitamin K. Results: There was a fall of vitamin D in 119 subjects and a rise in 164, while no change appeared in 7 participants. When vitamin D values went down between both assessments moments, the computed increase of mean corpuscular haemoglobin was significantly lower compared with the rise of mean corpuscular haemoglobin associated with a vitamin D elevation. When vitamin D declined, the computed fall of mean corpuscular volume fall was significantly lower compared with the decrease of mean corpuscular volume, when vitamin D rose. Positive correlations were found between differences of vitamin D and mean corpuscular haemoglobin, respectively mean corpuscular volume. Inverse relations appeared between disparities of vitamin D and erythrocytes, respectively haematocrit. Conclusions: The elevation of vitamin D plasma levels provides enhanced preconditions for a better tissue oxygenation on a cellular level.

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Viscoelastometry for detecting oral anticoagulants

Thrombosis Journal ◽

10.1186/s12959-021-00267-w ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Philipp Groene ◽

Daniela Wagner ◽

Tobias Kammerer ◽

Lars Kellert ◽

Andreas Giebl ◽

...

Keyword(s):

Healthy Volunteers ◽

Prospective Observational Study ◽

Oral Anticoagulants ◽

Plasma Concentrations ◽

Factor Xa ◽

Clotting Time ◽

Emergency Situations ◽

Tissue Plasminogen ◽

The Impact

Abstract Background Determination of anticoagulant therapy is of pronounced interest in emergency situations. However, routine tests do not provide sufficient insight. This study was performed to investigate the impact of anticoagulants on the results of viscoelastometric assays using the ClotPro device. Methods This prospective, observational study was conducted in patients receiving dabigatran, factor Xa (FXa)-inhibitors, phenprocoumon, low molecular weight heparin (LMWH) or unfractionated heparin (UFH) (local ethics committee approval number: 17–525-4). Healthy volunteers served as controls. Viscoelastometric assays were performed, including the extrinsic test (EX-test), intrinsic test (IN-test) Russel’s viper venom test (RVV-test), ecarin test (ECA-test), and the tissue plasminogen activator test (TPA-test). Results 70 patients and 10 healthy volunteers were recruited. Clotting time in the EX-test (CTEX-test) was significantly prolonged versus controls by dabigatran, FXa inhibitors and phenprocoumon. CTIN-test was prolonged by dabigatran, FXa inhibitors and UFH. Dabigatran, FXa inhibitors and UFH significantly prolonged CTRVV-test in comparison with controls (median 200, 207 and 289 vs 63 s, respectively; all p < 0.0005). Only dabigatran elicited a significant increase in CTECA-test compared to controls (median 307 vs 73 s; p < 0.0001). CTECA-test correlated strongly with dabigatran plasma concentration (measured by anti-IIa activity; r = 0.9970; p < 0.0001) and provided 100% sensitivity and 100% specificity for detecting dabigatran. Plasma concentrations (anti-XA activity) of FXa inhibitors correlated with CTRVV-test (r = 0.7998; p < 0.0001), and CTRVV-test provided 83% sensitivity and 64% specificity for detecting FXa inhibitors. Conclusions In emergency situations, ClotPro viscoelastometric assessment of whole-blood samples may help towards determining the presence and type of anticoagulant class that a patient is taking. Trial registration German clinical trials database ID: DRKS00015302.

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Antioxidants Promote Intestinal Tumor Progression in Mice

Antioxidants ◽

10.3390/antiox10020241 ◽

2021 ◽

Vol 10 (2) ◽

pp. 241

Author(s):

Zhiyuan V. Zou ◽

Kristell Le Gal ◽

Ahmed E. El Zowalaty ◽

Lara E. Pehlivanoglu ◽

Viktor Garellick ◽

...

Keyword(s):

Oxidative Stress ◽

Colorectal Cancer ◽

Tumor Progression ◽

Human Subjects ◽

Plasma Concentrations ◽

Intestinal Tumor ◽

Adenomatous Polyposis ◽

Intestinal Tumors ◽

The Impact

Dietary antioxidants and supplements are widely used to protect against cancer, even though it is now clear that antioxidants can promote tumor progression by helping cancer cells to overcome barriers of oxidative stress. Although recent studies have, in great detail, explored the role of antioxidants in lung and skin tumors driven by RAS and RAF mutations, little is known about the impact of antioxidant supplementation on other cancers, including Wnt-driven tumors originating from the gut. Here, we show that supplementation with the antioxidants N-acetylcysteine (NAC) and vitamin E promotes intestinal tumor progression in the ApcMin mouse model for familial adenomatous polyposis, a hereditary form of colorectal cancer, driven by Wnt signaling. Both antioxidants increased tumor size in early neoplasias and tumor grades in more advanced lesions without any impact on tumor initiation. Importantly, NAC treatment accelerated tumor progression at plasma concentrations comparable to those obtained in human subjects after prescription doses of the drug. These results demonstrate that antioxidants play an important role in the progression of intestinal tumors, which may have implications for patients with or predisposed to colorectal cancer.

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An In Vivo Predictive Dissolution Methodology (iPD Methodology) with a BCS Class IIb Drug Can Predict the In Vivo Bioequivalence Results: Etoricoxib Products

Pharmaceutics ◽

10.3390/pharmaceutics13040507 ◽

2021 ◽

Vol 13 (4) ◽

pp. 507

Author(s):

Isabel Gonzalez-Alvarez ◽

Marival Bermejo ◽

Yasuhiro Tsume ◽

Alejandro Ruiz-Picazo ◽

Marta Gonzalez-Alvarez ◽

...

Keyword(s):

Plasma Concentrations ◽

In Vitro Dissolution ◽

Case Examples ◽

Dissolution Studies ◽

Weak Bases ◽

Transit Times ◽

Class Iib ◽

The Impact

The purpose of this study was to predict in vivo performance of three oral products of Etoricoxib (Arcoxia® as reference and two generic formulations in development) by conducting in vivo predictive dissolution with GIS (Gastro Intestinal Simulator) and computational analysis. Those predictions were compared with the results from previous bioequivalence (BE) human studies. Product dissolution studies were performed using a computer-controlled multicompartmental dissolution device (GIS) equipped with three dissolution chambers, representing stomach, duodenum, and jejunum, with integrated transit times and secretion rates. The measured dissolved amounts were modelled in each compartment with a set of differential equations representing transit, dissolution, and precipitation processes. The observed drug concentration by in vitro dissolution studies were directly convoluted with permeability and disposition parameters from literature to generate the predicted plasma concentrations. The GIS was able to detect the dissolution differences among reference and generic formulations in the gastric chamber where the drug solubility is high (pH 2) while the USP 2 standard dissolution test at pH 2 did not show any difference. Therefore, the current study confirms the importance of multicompartmental dissolution testing for weak bases as observed for other case examples but also the impact of excipients on duodenal and jejunal in vivo behavior.

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Evaluating the Impact of Two Generalist Predators on the Leafhopper Erasmoneura vulnerata Population Density

Insects ◽

10.3390/insects12040321 ◽

2021 ◽

Vol 12 (4) ◽

pp. 321

Author(s):

Stefan Cristian Prazaru ◽

Giulia Zanettin ◽

Alberto Pozzebon ◽

Paola Tirello ◽

Francesco Toffoletto ◽

...

Keyword(s):

Field Experiments ◽

Field Studies ◽

Generalist Predators ◽

Predator Species ◽

Potted Plants ◽

Naturally Occurring ◽

Orius Majusculus ◽

Limited Effectiveness ◽

Pest Outbreaks ◽

The Impact

Outbreaks of the Nearctic leafhopper Erasmoneura vulnerata represent a threat to vinegrowers in Southern Europe, in particular in North-eastern Italy. The pest outbreaks are frequent in organic vineyards because insecticides labeled for organic viticulture show limited effectiveness towards leafhoppers. On the other hand, the naturally occurring predators and parasitoids of E. vulnerata in vineyards are often not able to keep leafhopper densities at acceptable levels for vine-growers. In this study, we evaluated the potential of two generalist, commercially available predators, Chrysoperla carnea and Orius majusculus, in suppressing E. vulnerata. Laboratory and semi-field experiments were carried out to evaluate both species’ predation capacity on E. vulnerata nymphs. The experiments were conducted on grapevine leaves inside Petri dishes (laboratory) and on potted and caged grapevines (semi-field); in both experiments, the leaves or potted plants were infested with E. vulnerata nymphs prior to predator releases. Both predator species exhibited a remarkable voracity and significantly reduced leafhopper densities in laboratory and semi-field experiments. Therefore, field studies were carried out over two growing seasons in two vineyards. We released 4 O. majusculus adults and 30 C. carnea larvae per m2 of canopy. Predator releases in vineyards reduced leafhopper densities by about 30% compared to the control plots. Results obtained in this study showed that the two predators have a potential to suppress the pest density, but more research is required to define appropriate predator–prey release ratios and release timing. Studies on intraguild interactions and competition with naturally occurring predators are also suggested.

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Impact of weight loss achieved through a multidisciplinary intervention on appetite in patients with severe obesity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00322.2017 ◽

2018 ◽

Vol 315 (1) ◽

pp. E91-E98 ◽

Cited By ~ 11

Author(s):

S. R. Coutinho ◽

J. F. Rehfeld ◽

J. J. Holst ◽

B. Kulseng ◽

C. Martins

Keyword(s):

Weight Loss ◽

Severe Obesity ◽

Peptide Yy ◽

Plasma Concentrations ◽

Cardiovascular Fitness ◽

Ghrelin Concentration ◽

Time Points ◽

Diet And Exercise ◽

The Impact

The impact of lifestyle-induced weight loss (WL) on appetite in patients with obesity remains controversial. This study aimed to assess the short- and long-term impact of WL achieved by diet and exercise on appetite in patients with obesity. Thirty-five (22 females) adults with severe obesity (body mass index: 42.5 ± 5.0 kg/m2) underwent a 2-yr WL program focusing on diet and exercise. Body weight (BW), cardiovascular fitness (V̇o2max), appetite feelings, and plasma concentrations of insulin, active ghrelin (AG), glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and cholecystokinin (CCK), in the fasting and postprandial states, were measured at baseline (B), week 4 (W4), and 1 and 2 yr (and average values for all fasting and postprandial time points computed). BW was significantly reduced and V̇o2max(ml·kg−1·min−1) increased at all time points compared with B (3.5, 8.1, and 8.4% WL and 7, 11, and 8% increase at W4 and 1 and 2 yr, respectively). Basal hunger and average hunger and desire to eat were significantly increased at 1 and 2 yr. Basal fullness was significantly increased at W4, and average ratings were reduced at 1 yr. Average AG and PYY were significantly increased, and insulin was reduced, at all time points compared with B. Average GLP-1 was reduced at W4, and CCK was increased at 2 yr. After lifestyle-induced WL, patients with severe obesity will, therefore, have to deal with increased hunger in the long term. In conclusion, sustained WL at 2 yr achieved with diet and exercise is associated with increased hunger feelings and ghrelin concentration but also increased postprandial concentrations of satiety hormones.

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MicroRNA-Regulated Signaling Pathways: Potential Biomarkers for Pancreatic Ductal Adenocarcinoma

Stresses ◽

10.3390/stresses1010004 ◽

2021 ◽

Vol 1 (1) ◽

pp. 30-47

Author(s):

Maria Mortoglou ◽

David Wallace ◽

Aleksandra Buha Buha Djordjevic ◽

Vladimir Djordjevic ◽

E. Damla Arisan ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Metabolic Stress ◽

Resistance Mechanisms ◽

Current Data ◽

Cellular Damage ◽

Ductal Adenocarcinoma ◽

Aberrant Expression ◽

Metabolic Alterations ◽

Limited Effectiveness ◽

The Impact

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and invasive type of pancreatic cancer (PCa) and is expected to be the second most common cause of cancer-associated deaths. The high mortality rate is due to the asymptomatic progression of the clinical features until the advanced stages of the disease and the limited effectiveness of the current therapeutics. Aberrant expression of several microRNAs (miRs/miRNAs) has been related to PDAC progression and thus they could be potential early diagnostic, prognostic, and/or therapeutic predictors for PDAC. miRs are small (18 to 24 nucleotides long) non-coding RNAs, which regulate the expression of key genes by targeting their 3′-untranslated mRNA region. Increased evidence has also suggested that the chemoresistance of PDAC cells is associated with metabolic alterations. Metabolic stress and the dysfunctionality of systems to compensate for the altered metabolic status of PDAC cells is the foundation for cellular damage. Current data have implicated multiple systems as hallmarks of PDAC development, such as glutamine redox imbalance, oxidative stress, and mitochondrial dysfunction. Hence, both the aberrant expression of miRs and dysregulation in metabolism can have unfavorable effects in several biological processes, such as apoptosis, cell proliferation, growth, survival, stress response, angiogenesis, chemoresistance, invasion, and migration. Therefore, due to these dismal statistics, it is crucial to develop beneficial therapeutic strategies based on an improved understanding of the biology of both miRs and metabolic mediators. This review focuses on miR-mediated pathways and therapeutic resistance mechanisms in PDAC and evaluates the impact of metabolic alterations in the progression of PDAC.

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Management of Oral Anti-Coagulation in Patients with Heart Failure—Insights from the ThrombEVAL Study

Thrombosis and Haemostasis ◽

10.1055/s-0038-1673380 ◽

2018 ◽

Vol 118 (11) ◽

pp. 1930-1939

Author(s):

Sebastian Göbel ◽

Jürgen Prochaska ◽

Lisa Eggebrecht ◽

Ronja Schmitz ◽

Claus Jünger ◽

...

Keyword(s):

Heart Failure ◽

Adverse Events ◽

Vitamin K Antagonists ◽

Plasma Concentrations ◽

Regular Care ◽

Increased Risk ◽

Patients With Heart Failure ◽

Specialized Care ◽

The Impact

AbstractPatients with heart failure (HF) are frequently anti-coagulated with vitamin K-antagonists (VKAs). The use of long-acting VKA may be preferable for HF patients due to higher stability of plasma concentrations. However, evidence on phenprocoumon-based oral anti-coagulation (OAC) therapy in HF is scarce. The aim of this study was to assess the impact of the presence of HF on quality of phenprocoumon-based OAC and the subsequent clinical outcome. Quality of OAC therapy and the incidence of adverse events were analysed in a cohort of regular care (n = 2,011) from the multi-centre thrombEVAL study program (NCT01809015) stratified by the presence of HF. To assess the modifiability of outcome, results were compared with data from individuals receiving specialized care for anti-coagulation (n = 760). Overall, the sample comprised of 813 individuals with HF and 1,160 subjects without HF in the regular care cohort. Quality of OAC assessed by time in therapeutic range (TTR) was 66.1% (47.8%/82.8%) for patients with HF and 70.6% (52.1%/85.9%) for those without HF (p = 0.0046). Stratification for New York Heart Classification (NYHA)-class demonstrated a lower TTR with higher NYHA classes: TTRNYHA-I 69.6% (49.4%/85.6%), TTRNYHA-II 66.5% (50.1%/82.9%) and TTRNYHA-≥III 61.8% (43.1%/79.9%). This translated into a worse net clinical benefit outcome for HF (hazard ratio [HR] 1.63 [1.31/2.02]; p < 0.0001) and an increased risk of bleeding (HR 1.40 [1.04/1.89]; p = 0.028). Management in a specialized coagulation service resulted in an improvement of all, TTR (∆+12.5% points), anti-coagulation-specific and non-specific outcome of HF individuals. In conclusion, HF is an independent risk factor for low quality of OAC therapy translating into an increased risk for adverse events, which can be mitigated by specialized care.

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