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Patients with chronic kidney disease (CKD) suffer from arterial media calcification and a disturbed bone metabolism. Tissue-nonspecific alkaline phosphatase (TNAP) hydrolyzes the calcification inhibitor pyrophosphate (PPi) into inorganic phosphate (Pi) and thereby stimulates arterial media calcification as well as physiological bone mineralization. This study investigates whether the TNAP inhibitor SBI-425, PPi or the combination of both inhibit arterial media calcification in an 0.75% adenine rat model of CKD. Treatments started with the induction of CKD, including (i) rats with normal renal function (control diet) treated with vehicle and CKD rats treated with either (ii) vehicle, (iii) 10 mg/kg/day SBI-425, (iv) 120 µmol/kg/day PPi and (v) 120 µmol/kg/day PPi and 10 mg/kg/day SBI-425. All CKD groups developed a stable chronic renal failure reflected by hyperphosphatemia, hypocalcemia and high serum creatinine levels. CKD induced arterial media calcification and bone metabolic defects. All treatments, except for SBI-425 alone, blocked CKD-related arterial media calcification. More important, SBI-425 alone and in combination with PPi increased osteoid area pointing to a less efficient bone mineralization. Clearly, potential side effects on bone mineralization will need to be assessed in any clinical trial aimed at modifying the Pi/PPi ratio in CKD patients who already suffer from a compromised bone status.
Britt Opdebeeck; Ellen Neven; José Millán; Anthony Pinkerton; Patrick D’Haese; Anja Verhulst. Chronic Kidney Disease-Induced Arterial Media Calcification in Rats Prevented by Tissue Non-Specific Alkaline Phosphatase Substrate Supplementation Rather Than Inhibition of the Enzyme. Pharmaceutics 2021, 13, 1138 .
AMA StyleBritt Opdebeeck, Ellen Neven, José Millán, Anthony Pinkerton, Patrick D’Haese, Anja Verhulst. Chronic Kidney Disease-Induced Arterial Media Calcification in Rats Prevented by Tissue Non-Specific Alkaline Phosphatase Substrate Supplementation Rather Than Inhibition of the Enzyme. Pharmaceutics. 2021; 13 (8):1138.
Chicago/Turabian StyleBritt Opdebeeck; Ellen Neven; José Millán; Anthony Pinkerton; Patrick D’Haese; Anja Verhulst. 2021. "Chronic Kidney Disease-Induced Arterial Media Calcification in Rats Prevented by Tissue Non-Specific Alkaline Phosphatase Substrate Supplementation Rather Than Inhibition of the Enzyme." Pharmaceutics 13, no. 8: 1138.
Ana Carina Ferreira; Martine Cohen-Solal; Patrick C. D’Haese; Aníbal Ferreira. The Role of Bone Biopsy in the Management of CKD-MBD: CKD-Related Osteoporosis or CKD-MBD/Osteoporosis? Calcified Tissue International 2021, 109, 112 -112.
AMA StyleAna Carina Ferreira, Martine Cohen-Solal, Patrick C. D’Haese, Aníbal Ferreira. The Role of Bone Biopsy in the Management of CKD-MBD: CKD-Related Osteoporosis or CKD-MBD/Osteoporosis? Calcified Tissue International. 2021; 109 (1):112-112.
Chicago/Turabian StyleAna Carina Ferreira; Martine Cohen-Solal; Patrick C. D’Haese; Aníbal Ferreira. 2021. "The Role of Bone Biopsy in the Management of CKD-MBD: CKD-Related Osteoporosis or CKD-MBD/Osteoporosis?" Calcified Tissue International 109, no. 1: 112-112.
A bone biopsy is still considered the gold standard for diagnosis of renal osteodystrophy. It allows to measure both static and dynamic parameters of bone remodeling and is the only method able to evaluate mineralization and allows analysis of both cortical and trabecular bone. Although bone volume can be measured indirectly by dual-energy X-ray absorptiometry, mineralization defects, bone metal deposits, cellular number/activity, and even turnover abnormalities are difficult to determine by techniques other than qualitative bone histomorphometry. In this review, we evaluate the role of bone biopsy in the clinical practice.
Ana Carina Ferreira; Martine Cohen-Solal; Patrick C. D’Haese; Aníbal Ferreira. The Role of Bone Biopsy in the Management of CKD-MBD. Calcified Tissue International 2021, 108, 528 -538.
AMA StyleAna Carina Ferreira, Martine Cohen-Solal, Patrick C. D’Haese, Aníbal Ferreira. The Role of Bone Biopsy in the Management of CKD-MBD. Calcified Tissue International. 2021; 108 (4):528-538.
Chicago/Turabian StyleAna Carina Ferreira; Martine Cohen-Solal; Patrick C. D’Haese; Aníbal Ferreira. 2021. "The Role of Bone Biopsy in the Management of CKD-MBD." Calcified Tissue International 108, no. 4: 528-538.
Arterial calcification, the deposition of calcium-phosphate crystals in the extracellular matrix, resembles physiological bone mineralization. It is well-known that extracellular nucleotides regulate bone homeostasis raising an emerging interest in the role of these molecules on arterial calcification. The purinergic independent pathway involves the enzymes ecto-nucleotide pyrophosphatase/phosphodiesterases (NPPs), ecto-nucleoside triphosphate diphosphohydrolases (NTPDases), 5′-nucleotidase and alkaline phosphatase. These regulate the production and breakdown of the calcification inhibitor—pyrophosphate and the calcification stimulator—inorganic phosphate, from extracellular nucleotides. Maintaining ecto-nucleotidase activities in a well-defined range is indispensable as enzymatic hyper- and hypo-expression has been linked to arterial calcification. The purinergic signaling dependent pathway focusses on the activation of purinergic receptors (P1, P2X and P2Y) by extracellular nucleotides. These receptors influence arterial calcification by interfering with the key molecular mechanisms underlying this pathology, including the osteogenic switch and apoptosis of vascular cells and possibly, by favoring the phenotypic switch of vascular cells towards an adipogenic phenotype, a recent, novel hypothesis explaining the systemic prevention of arterial calcification. Selective compounds influencing the activity of ecto-nucleotidases and purinergic receptors, have recently been developed to treat arterial calcification. However, adverse side-effects on bone mineralization are possible as these compounds reasonably could interfere with physiological bone mineralization.
Britt Opdebeeck; Isabel R. Orriss; Ellen Neven; Patrick C. D’Haese; Anja Verhulst. Extracellular Nucleotides Regulate Arterial Calcification by Activating Both Independent and Dependent Purinergic Receptor Signaling Pathways. International Journal of Molecular Sciences 2020, 21, 7636 .
AMA StyleBritt Opdebeeck, Isabel R. Orriss, Ellen Neven, Patrick C. D’Haese, Anja Verhulst. Extracellular Nucleotides Regulate Arterial Calcification by Activating Both Independent and Dependent Purinergic Receptor Signaling Pathways. International Journal of Molecular Sciences. 2020; 21 (20):7636.
Chicago/Turabian StyleBritt Opdebeeck; Isabel R. Orriss; Ellen Neven; Patrick C. D’Haese; Anja Verhulst. 2020. "Extracellular Nucleotides Regulate Arterial Calcification by Activating Both Independent and Dependent Purinergic Receptor Signaling Pathways." International Journal of Molecular Sciences 21, no. 20: 7636.
Introduction Sucroferric oxyhydroxide (PA21) is an efficacious, well-tolerated iron-based phosphate binder and a promising alternative to existing compounds. We compared the effects of PA21 with those of a conventional phosphate binder on renal function, mineral homeostasis and vascular calcification in a chronic kidney disease–mineral and bone disorder (CKD-MBD) rat model. Methods To induce stable renal failure, rats were administered a 0.25% adenine diet for 8 weeks. Concomitantly, rats were treated with vehicle, 2.5 g/kg/day PA21, 5.0 g/kg/day PA21 or 3.0 g/kg/day calcium carbonate (CaCO3). Renal function and calcium/phosphorus/iron metabolism were evaluated during the study course. Renal fibrosis, inflammation, vascular calcifications and bone histomorphometry were quantified. Results Rats treated with 2.5 or 5.0 g/kg/day PA21 showed significantly lower serum creatinine and phosphorus and higher ionized calcium levels after 8 weeks of treatment compared with vehicle-treated rats. The better preserved renal function with PA21 went along with less severe anaemia, which was not observed with CaCO3. Both PA21 doses, in contrast to CaCO3, prevented a dramatic increase in fibroblast growth factor (FGF)-23 and significantly reduced the vascular calcium content while both compounds ameliorated CKD-related hyperparathyroid bone. Conclusions PA21 treatment prevented an increase in serum FGF-23 and had, aside from its phosphate-lowering capacity, a beneficial impact on renal function decline (as assessed by the renal creatinine clearance) and related disorders. The protective effect of this iron-based phosphate binder on the kidney in rats, together with its low pill burden in humans, led us to investigate its use in patients with impaired renal function not yet on dialysis.
Ellen Neven; Raphaëlle Corremans; Benjamin A Vervaet; Felix Funk; Sebastian Walpen; Geert J Behets; Patrick C D’Haese; Anja Verhulst. Renoprotective effects of sucroferric oxyhydroxide in a rat model of chronic renal failure. Nephrology Dialysis Transplantation 2020, 35, 1689 -1699.
AMA StyleEllen Neven, Raphaëlle Corremans, Benjamin A Vervaet, Felix Funk, Sebastian Walpen, Geert J Behets, Patrick C D’Haese, Anja Verhulst. Renoprotective effects of sucroferric oxyhydroxide in a rat model of chronic renal failure. Nephrology Dialysis Transplantation. 2020; 35 (10):1689-1699.
Chicago/Turabian StyleEllen Neven; Raphaëlle Corremans; Benjamin A Vervaet; Felix Funk; Sebastian Walpen; Geert J Behets; Patrick C D’Haese; Anja Verhulst. 2020. "Renoprotective effects of sucroferric oxyhydroxide in a rat model of chronic renal failure." Nephrology Dialysis Transplantation 35, no. 10: 1689-1699.
Histomorphometric analysis of a transiliac bone biopsy is the gold standard for the diagnosis of renal osteodystrophy (ROD). This procedure is costly, invasive and usually performed with a trephine with an internal diameter of 7.5 mm. Our objective was to evaluate the accuracy of ROD diagnosis on halved histological bone sections to determine if they are comparable to the standard 7.5 mm samples. We included 68 bone biopsies performed in CKD patients for diagnostic purposes with a 7.5 mm diameter trephine. Quantitative histomorphometric analysis of the whole bone samples was performed including assessment of bone mineralization, turnover and volume. Each histological section (representing the whole 7.5 mm diameter biopsy) was then divided lengthwise in two hemisections (representing the 3.5 mm diameter biopsy). Histomorphometric analysis was repeated this time on the two hemibiopsies for each sample, blinded from initial results. Diagnoses were classified as osteitis fibrosa, adynamic bone disease, mixed uremic bone disease, osteomalacia or other. Correlations between the whole sample and the hemibiopsies for each parameter were studied. Concordance between the various bone parameters and final ROD diagnosis obtained from the whole section versus the two hemi sections was evaluated. Highly significant correlations were found between parameters measured on the whole section and the corresponding hemisections, with r coefficient of 0.98 for osteoid surface and thickness and bone formation rate, 0.97 for osteoclast surface, and 0.96 for bone volume (p < 0.001). Final diagnosis was in full accordance between the whole biopsy and the two corresponding hemi-biopsies in 91% of cases. Accurate diagnosis of ROD type was obtained by evaluation of bone surface areas of 3 mm diameter. These data suggest that small invasive bone biopsies might provide accurate ROD diagnostics while decreasing both invasiveness and cost of the procedure.
Etienne Novel-Catin; Solenne Pelletier; Denis Fouque; Jean-Paul Roux; Roland Chapurlat; Patrick D'Haese; Geert Behets; Peter Evenepoel; Thomas L. Nickolas; Marie-Hélène Lafage-Proust. Quantitative histomorphometric analysis of halved iliac crest bone biopsies yield comparable ROD diagnosis as full 7.5mm wide samples. Bone 2020, 138, 115460 .
AMA StyleEtienne Novel-Catin, Solenne Pelletier, Denis Fouque, Jean-Paul Roux, Roland Chapurlat, Patrick D'Haese, Geert Behets, Peter Evenepoel, Thomas L. Nickolas, Marie-Hélène Lafage-Proust. Quantitative histomorphometric analysis of halved iliac crest bone biopsies yield comparable ROD diagnosis as full 7.5mm wide samples. Bone. 2020; 138 ():115460.
Chicago/Turabian StyleEtienne Novel-Catin; Solenne Pelletier; Denis Fouque; Jean-Paul Roux; Roland Chapurlat; Patrick D'Haese; Geert Behets; Peter Evenepoel; Thomas L. Nickolas; Marie-Hélène Lafage-Proust. 2020. "Quantitative histomorphometric analysis of halved iliac crest bone biopsies yield comparable ROD diagnosis as full 7.5mm wide samples." Bone 138, no. : 115460.
Arterial media calcification is frequently seen in elderly and patients with chronic kidney disease (CKD), diabetes and osteoporosis. Pyrophosphate is a well-known calcification inhibitor that binds to nascent hydroxyapatite crystals and prevents further incorporation of inorganic phosphate into these crystals. However, the enzyme tissue-nonspecific alkaline phosphatase (TNAP), which is expressed in calcified arteries, degrades extracellular pyrophosphate into phosphate ions, by which pyrophosphate loses its ability to block vascular calcification. Here, we aimed to evaluate whether pharmacological TNAP inhibition is able to prevent the development of arterial calcification in a rat model of warfarin-induced vascular calcification. To investigate the effect of the pharmacological TNAP inhibitor SBI-425 on vascular calcification and bone metabolism, a 0.30% warfarin rat model was used. Warfarin exposure resulted in distinct calcification in the aorta and peripheral arteries. Daily administration of the TNAP inhibitor SBI-425 (10 mg/kg/day) for 7 weeks significantly reduced vascular calcification as indicated by a significant decrease in calcium content in the aorta (vehicle 3.84 ± 0.64 mg calcium/g wet tissue vs TNAP inhibitor 0.70 ± 0.23 mg calcium/g wet tissue) and peripheral arteries and a distinct reduction in area % calcification on Von Kossa stained aortic sections as compared to vehicle. Administration of SBI-425 resulted in decreased bone formation rate and mineral apposition rate, and increased osteoid maturation time and this without significant changes in osteoclast- and eroded perimeter. Administration of TNAP inhibitor SBI-425 significantly reduced the calcification in the aorta and peripheral arteries of a rat model of warfarin-induced vascular calcification. However, suppression of TNAP activity should be limited in order to maintain adequate physiological bone mineralization.
Britt Opdebeeck; Ellen Neven; José Luis Millán; Anthony B. Pinkerton; Patrick C. D'Haese; Anja Verhulst. Pharmacological TNAP inhibition efficiently inhibits arterial media calcification in a warfarin rat model but deserves careful consideration of potential physiological bone formation/mineralization impairment. Bone 2020, 137, 115392 .
AMA StyleBritt Opdebeeck, Ellen Neven, José Luis Millán, Anthony B. Pinkerton, Patrick C. D'Haese, Anja Verhulst. Pharmacological TNAP inhibition efficiently inhibits arterial media calcification in a warfarin rat model but deserves careful consideration of potential physiological bone formation/mineralization impairment. Bone. 2020; 137 ():115392.
Chicago/Turabian StyleBritt Opdebeeck; Ellen Neven; José Luis Millán; Anthony B. Pinkerton; Patrick C. D'Haese; Anja Verhulst. 2020. "Pharmacological TNAP inhibition efficiently inhibits arterial media calcification in a warfarin rat model but deserves careful consideration of potential physiological bone formation/mineralization impairment." Bone 137, no. : 115392.
Sclerostin, a 22-kDa glycoprotein that is mainly secreted by the osteocytes, is a soluble inhibitor of canonical Wnt signaling. Therefore, when present at increased concentrations, it leads to an increased bone resorption and decreased bone formation. Serum sclerostin levels are known to be increased in the elderly and in patients with chronic kidney disease. In these patient populations, there is a high incidence of ectopic cardiovascular calcification. These calcifications are strongly associated with cardiovascular morbidity and mortality. Although data are still controversial, it is likely that there is a link between ectopic calcification and serum sclerostin levels. The main question, however, remains whether sclerostin exerts either a protective or deleterious role in the ectopic calcification process.
Annelies De Maré; Patrick C. D’Haese; Anja Verhulst. The Role of Sclerostin in Bone and Ectopic Calcification. International Journal of Molecular Sciences 2020, 21, 3199 .
AMA StyleAnnelies De Maré, Patrick C. D’Haese, Anja Verhulst. The Role of Sclerostin in Bone and Ectopic Calcification. International Journal of Molecular Sciences. 2020; 21 (9):3199.
Chicago/Turabian StyleAnnelies De Maré; Patrick C. D’Haese; Anja Verhulst. 2020. "The Role of Sclerostin in Bone and Ectopic Calcification." International Journal of Molecular Sciences 21, no. 9: 3199.
The protein-bound uremic toxins, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), are considered to be harmful vascular toxins. Arterial media calcification, or the deposition of calcium phosphate crystals in the arteries, contributes significantly to cardiovascular complications, including left ventricular hypertrophy, hypertension, and impaired coronary perfusion in the elderly and patients with chronic kidney disease (CKD) and diabetes. Recently, we reported that both IS and PCS trigger moderate to severe calcification in the aorta and peripheral vessels of CKD rats. This review describes the molecular and cellular mechanisms by which these uremic toxins induce arterial media calcification. A complex interplay between inflammation, coagulation, and lipid metabolism pathways, influenced by epigenetic factors, is crucial in IS/PCS-induced arterial media calcification. High levels of glucose are linked to these events, suggesting that a good balance between glucose and lipid levels might be important. On the cellular level, effects on endothelial cells, which act as the primary sensors of circulating pathological triggers, might be as important as those on vascular smooth muscle cells. Endothelial dysfunction, provoked by IS and PCS triggered oxidative stress, may be considered a key event in the onset and development of arterial media calcification. In this review a number of important outstanding questions such as the role of miRNA’s, phenotypic switching of both endothelial and vascular smooth muscle cells and new types of programmed cell death in arterial media calcification related to protein-bound uremic toxins are put forward and discussed.
Britt Opdebeeck; Patrick C. D’Haese; Anja Verhulst. Molecular and Cellular Mechanisms that Induce Arterial Calcification by Indoxyl Sulfate and P-Cresyl Sulfate. Toxins 2020, 12, 58 .
AMA StyleBritt Opdebeeck, Patrick C. D’Haese, Anja Verhulst. Molecular and Cellular Mechanisms that Induce Arterial Calcification by Indoxyl Sulfate and P-Cresyl Sulfate. Toxins. 2020; 12 (1):58.
Chicago/Turabian StyleBritt Opdebeeck; Patrick C. D’Haese; Anja Verhulst. 2020. "Molecular and Cellular Mechanisms that Induce Arterial Calcification by Indoxyl Sulfate and P-Cresyl Sulfate." Toxins 12, no. 1: 58.
Arterial media calcification refers to ectopic mineralization in the arterial wall and favors arterial stiffness and cardiovascular events. Patients with chronic kidney disease (CKD), diabetes or osteoporosis are highly vulnerable to the development of arterial media calcifications. Tissue non‐specific alkaline phosphatase (TNAP) is upregulated in calcified arteries and plays a key role in the degradation of the calcification inhibitor pyrophosphate into inorganic phosphate ions. A recent study published in The Journal of Pathology showed that an oral dosage of 10 or 30 mg/kg/day SBI‐425, a selective TNAP‐inhibitor, inhibited the development of arterial media calcification in mice suffering from CKD, without affecting bone mineralization. Their results indicated that SBI‐425 is an effective and safe treatment for arterial media calcification. However, additional studies regarding the effect of TNAP‐inhibitor SBI‐425 on the progression and even the reversion of pre‐existing pathological arterial media calcifications without affecting physiological bone mineralization are deserved. Furthermore, investigating the extent to which SBI‐425 inhibits arterial calcification in a non‐CKD context would be of particular interest to treat this co‐morbidity in diabetes and osteoporosis patients. This article is protected by copyright. All rights reserved.
Britt Opdebeeck; Patrick C D'haese; Anja Verhulst. Inhibition of tissue non‐specific alkaline phosphatase; a novel therapy against arterial media calcification? The Journal of Pathology 2019, 250, 248 -250.
AMA StyleBritt Opdebeeck, Patrick C D'haese, Anja Verhulst. Inhibition of tissue non‐specific alkaline phosphatase; a novel therapy against arterial media calcification? The Journal of Pathology. 2019; 250 (3):248-250.
Chicago/Turabian StyleBritt Opdebeeck; Patrick C D'haese; Anja Verhulst. 2019. "Inhibition of tissue non‐specific alkaline phosphatase; a novel therapy against arterial media calcification?" The Journal of Pathology 250, no. 3: 248-250.
Mounting evidence indicates that sclerostin, a well-known inhibitor of bone formation, may qualify as a clinically relevant biomarker of chronic kidney disease-related mineral and bone disorder (CKD-MBD), including abnormal mineral and bone metabolism and extraskeletal calcification. For this purpose, in this study we investigate the extent to which circulating sclerostin, skeletal sclerostin expression, bone histomorphometric parameters, and serum markers of bone metabolism associate with each other. Bone biopsies and serum samples were collected in a cohort of 68 end-stage kidney disease (ESKD) patients. Serum sclerostin levels were measured using 4 different commercially available assays. Skeletal sclerostin expression was evaluated on immunohistochemically stained bone sections. Quantitative bone histomorphometry was performed on Goldner stained tissue sections. Different serum markers of bone metabolism were analyzed using in-house techniques or commercially available assays. Despite large inter-assay differences for circulating sclerostin, results obtained with the 4 assays under study closely correlated with each other, whilst moderate significant correlations with skeletal sclerostin expression were also found. Both skeletal and circulating sclerostin negatively correlated with histomorphometric bone and serum parameters reflecting bone formation and turnover. In this study, the unique combined evaluation of bone sclerostin expression, bone histomorphometry, bone biomarkers, and serum sclerostin levels, as assessed by 4 different assays, demonstrated that sclerostin may qualify as a clinically relevant marker of disturbed bone metabolism in ESKD patients.
Annelies De Maré; Anja Verhulst; Etienne Cavalier; Pierre Delanaye; Geert J. Behets; Bjorn Meijers; Dirk Kuypers; Patrick C. D’Haese; Pieter Evenepoel; Maré; D’ Haese. Clinical Inference of Serum and Bone Sclerostin Levels in Patients with End-Stage Kidney Disease. Journal of Clinical Medicine 2019, 8, 2027 .
AMA StyleAnnelies De Maré, Anja Verhulst, Etienne Cavalier, Pierre Delanaye, Geert J. Behets, Bjorn Meijers, Dirk Kuypers, Patrick C. D’Haese, Pieter Evenepoel, Maré, D’ Haese. Clinical Inference of Serum and Bone Sclerostin Levels in Patients with End-Stage Kidney Disease. Journal of Clinical Medicine. 2019; 8 (12):2027.
Chicago/Turabian StyleAnnelies De Maré; Anja Verhulst; Etienne Cavalier; Pierre Delanaye; Geert J. Behets; Bjorn Meijers; Dirk Kuypers; Patrick C. D’Haese; Pieter Evenepoel; Maré; D’ Haese. 2019. "Clinical Inference of Serum and Bone Sclerostin Levels in Patients with End-Stage Kidney Disease." Journal of Clinical Medicine 8, no. 12: 2027.
Arterial media calcification and arterial stiffness are independent predictors of cardiovascular mortality. Both processes reinforce one another, creating a vicious cycle in which transdifferentiation of endothelial cells and vascular smooth muscle cells play a central role. Physiological functioning of vascular smooth muscle cells in the arterial medial layer greatly depends on normal endothelial cell behavior. Endothelial or intimal layer cells are the primary sensors of pathological triggers circulating in the blood during, for example, ageing or inflammation, and often can be seen as initiators of this vicious cycle. As such, the search for treatment of arterial media calcification, which until now has been mainly concentrated at the level of the vascular smooth cell, may need to be expanded to intimal layer targets.
Geoffrey Van Den Bergh; Britt Opdebeeck; Patrick C. D’Haese; Anja Verhulst. The Vicious Cycle of Arterial Stiffness and Arterial Media Calcification. Trends in Molecular Medicine 2019, 25, 1133 -1146.
AMA StyleGeoffrey Van Den Bergh, Britt Opdebeeck, Patrick C. D’Haese, Anja Verhulst. The Vicious Cycle of Arterial Stiffness and Arterial Media Calcification. Trends in Molecular Medicine. 2019; 25 (12):1133-1146.
Chicago/Turabian StyleGeoffrey Van Den Bergh; Britt Opdebeeck; Patrick C. D’Haese; Anja Verhulst. 2019. "The Vicious Cycle of Arterial Stiffness and Arterial Media Calcification." Trends in Molecular Medicine 25, no. 12: 1133-1146.
Among several other eutrophication management tools, Phoslock®, a lanthanum modified bentonite (LMB) clay, is now frequently used. Concerns have been raised as to whether exposure to Phoslock®-treated water may lead to lanthanum accumulation/toxicity in both animals and humans. In the present experimental study, rats were administered lanthanum orally as either lanthanum carbonate, lanthanum chloride or Phoslock® at doses of either 0.5 or 17 mg/L during 10 weeks. Controls received vehicle. The gastrointestinal absorption and tissue distribution of lanthanum was investigated. Extremely strict measures were implemented to avoid cross-contamination between different tissues or animals. Results showed no differences in gastrointestinal absorption between the different compounds under study as reflected by the serum lanthanum levels and concentrations found in the brain, bone, heart, spleen, lung, kidney and testes. At sacrifice, significant but equally increased lanthanum concentrations versus vehicle were observed in the liver for the highest dose of each compound which however, remained several orders of magnitude below the liver lanthanum concentration previously measured after long-term therapeutic administration of lanthanum carbonate and for which no hepatotoxicity was noticed in humans. In conclusion, (i) the use of LMB does not pose a toxicity risk (ii) gastrointestinal absorption of lanthanum is minimal and independent on the type of the compound, (iii) with exception of the liver, no significant increase in lanthanum levels is observed in the various organs under study, (iv) based on previous studies, the slightly increased liver lanthanum levels observed in a worst case scenario do not hold any risk of hepatotoxicity.
Geert J. Behets; Kayawe Valentine Mubiana; Ludwig Lamberts; Karin Finsterle; Nigel Traill; Ronny Blust; Patrick C. D'Haese. Use of lanthanum for water treatment A matter of concern? Chemosphere 2019, 239, 124780 .
AMA StyleGeert J. Behets, Kayawe Valentine Mubiana, Ludwig Lamberts, Karin Finsterle, Nigel Traill, Ronny Blust, Patrick C. D'Haese. Use of lanthanum for water treatment A matter of concern? Chemosphere. 2019; 239 ():124780.
Chicago/Turabian StyleGeert J. Behets; Kayawe Valentine Mubiana; Ludwig Lamberts; Karin Finsterle; Nigel Traill; Ronny Blust; Patrick C. D'Haese. 2019. "Use of lanthanum for water treatment A matter of concern?" Chemosphere 239, no. : 124780.
Sclerostin is a well-known inhibitor of bone formation that acts on Wnt/β-catenin signaling. This manuscript considers the possible role of sclerostin in vascular calcification, a process that shares many similarities with physiological bone formation. Rats were exposed to a warfarin-containing diet to induce vascular calcification. Vascular smooth muscle cell transdifferentiation, vascular calcification grade, and bone histomorphometry were examined. The presence and/or production of sclerostin was investigated in serum, aorta, and bone. Calcified human aortas were investigated to substantiate clinical relevance. Warfarin-exposed rats developed vascular calcifications in a time-dependent manner which went along with a progressive increase in serum sclerostin levels. Both osteogenic and adipogenic pathways were upregulated in calcifying vascular smooth muscle cells, as well as sclerostin mRNA and protein levels. Evidence for the local vascular action of sclerostin was found both in human and rat calcified aortas. Warfarin exposure led to a mildly decreased bone and mineralized areas. Osseous sclerostin production and bone turnover did not change significantly. This study showed local production of sclerostin in calcified vessels, which may indicate a negative feedback mechanism to prevent further calcification. Furthermore, increased levels of serum sclerostin, probably originating from excessive local production in calcified vessels, may contribute to the linkage between vascular pathology and impaired bone mineralization.
Annelies De Maré; Stuart Maudsley; Abdelkrim Azmi; Jhana O. Hendrickx; Britt Opdebeeck; Ellen Neven; Patrick C D’Haese; Anja Verhulst. Sclerostin as Regulatory Molecule in Vascular Media Calcification and the Bone-Vascular Axis. Toxins 2019, 11, 428 .
AMA StyleAnnelies De Maré, Stuart Maudsley, Abdelkrim Azmi, Jhana O. Hendrickx, Britt Opdebeeck, Ellen Neven, Patrick C D’Haese, Anja Verhulst. Sclerostin as Regulatory Molecule in Vascular Media Calcification and the Bone-Vascular Axis. Toxins. 2019; 11 (7):428.
Chicago/Turabian StyleAnnelies De Maré; Stuart Maudsley; Abdelkrim Azmi; Jhana O. Hendrickx; Britt Opdebeeck; Ellen Neven; Patrick C D’Haese; Anja Verhulst. 2019. "Sclerostin as Regulatory Molecule in Vascular Media Calcification and the Bone-Vascular Axis." Toxins 11, no. 7: 428.
BackgroundProtein-bound uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (PCS) have been associated with cardiovascular morbidity and mortality in patients with CKD. However, direct evidence for a role of these toxins in CKD-related vascular calcification has not been reported.MethodsTo study early and late vascular alterations by toxin exposure, we exposed CKD rats to vehicle, IS (150 mg/kg per day), or PCS (150 mg/kg per day) for either 4 days (short-term exposure) or 7 weeks (long-term exposure). We also performed unbiased proteomic analyses of arterial samples coupled to functional bioinformatic annotation analyses to investigate molecular signaling events associated with toxin-mediated arterial calcification.ResultsLong-term exposure to either toxin at serum levels similar to those experienced by patients with CKD significantly increased calcification in the aorta and peripheral arteries. Our analyses revealed an association between calcification events, acute-phase response signaling, and coagulation and glucometabolic signaling pathways, whereas escape from toxin-induced calcification was linked with liver X receptors and farnesoid X/liver X receptor signaling pathways. Additional metabolic linkage to these pathways revealed that IS and PCS exposure engendered a prodiabetic state evidenced by elevated resting glucose and reduced GLUT1 expression. Short-term exposure to IS and PCS (before calcification had been established) showed activation of inflammation and coagulation signaling pathways in the aorta, demonstrating that these signaling pathways are causally implicated in toxin-induced arterial calcification.ConclusionsIn CKD, both IS and PCS directly promote vascular calcification via activation of inflammation and coagulation pathways and were strongly associated with impaired glucose homeostasis.
Britt Opdebeeck; Stuart Maudsley; Abdelkrim Azmi; Annelies De Maré; Wout De Leger; Bjorn Meijers; Anja Verhulst; Pieter Evenepoel; Patrick C. D’Haese; Ellen Neven. Indoxyl Sulfate and p-Cresyl Sulfate Promote Vascular Calcification and Associate with Glucose Intolerance. Journal of the American Society of Nephrology 2019, 30, 751 -766.
AMA StyleBritt Opdebeeck, Stuart Maudsley, Abdelkrim Azmi, Annelies De Maré, Wout De Leger, Bjorn Meijers, Anja Verhulst, Pieter Evenepoel, Patrick C. D’Haese, Ellen Neven. Indoxyl Sulfate and p-Cresyl Sulfate Promote Vascular Calcification and Associate with Glucose Intolerance. Journal of the American Society of Nephrology. 2019; 30 (5):751-766.
Chicago/Turabian StyleBritt Opdebeeck; Stuart Maudsley; Abdelkrim Azmi; Annelies De Maré; Wout De Leger; Bjorn Meijers; Anja Verhulst; Pieter Evenepoel; Patrick C. D’Haese; Ellen Neven. 2019. "Indoxyl Sulfate and p-Cresyl Sulfate Promote Vascular Calcification and Associate with Glucose Intolerance." Journal of the American Society of Nephrology 30, no. 5: 751-766.
Over the past decades metformin has been the optimal first-line treatment for type 2 diabetes mellitus (T2DM). Only in the last few years, it has become increasingly clear that metformin exerts benign pleiotropic actions beyond its prescribed use and ongoing investigations focus on a putative beneficial impact of metformin on the kidney. Both acute kidney injury (AKI) and chronic kidney disease (CKD), two major renal health issues, often result in the need for renal replacement therapy (dialysis or transplantation) with a high socio-economic impact for the patients. Unfortunately, to date, effective treatment directly targeting the kidney is lacking. Metformin has been shown to exert beneficial effects on the kidney in various clinical trials and experimental studies performed in divergent rodent models representing different types of renal diseases going from AKI to CKD. Despite growing evidence on metformin as a candidate drug for renal diseases, in-depth research is imperative to unravel the molecular signaling pathways responsible for metformin’s renoprotective actions. This review will discuss the current state-of-the-art literature on clinical and preclinical data, and put forward potential cellular mechanisms and molecular pathways by which metformin ameliorates AKI/CKD.
Raphaëlle Corremans; Benjamin A. Vervaet; Patrick C. D’Haese; Ellen Neven; Anja Verhulst. Metformin: A Candidate Drug for Renal Diseases. International Journal of Molecular Sciences 2018, 20, 42 .
AMA StyleRaphaëlle Corremans, Benjamin A. Vervaet, Patrick C. D’Haese, Ellen Neven, Anja Verhulst. Metformin: A Candidate Drug for Renal Diseases. International Journal of Molecular Sciences. 2018; 20 (1):42.
Chicago/Turabian StyleRaphaëlle Corremans; Benjamin A. Vervaet; Patrick C. D’Haese; Ellen Neven; Anja Verhulst. 2018. "Metformin: A Candidate Drug for Renal Diseases." International Journal of Molecular Sciences 20, no. 1: 42.
The use of geo-engineering materials to manage phosphorus in lakes has increased in recent years with aluminium and lanthanum based materials being most commonly applied. Hence the potential impact of the use of these compounds on human health is receiving growing interest. This review seeks to understand, evaluate and compare potential unintended consequences on human health and ecotoxicological risks associated with the use of lanthanum- and aluminium-based materials to modify chemical and ecological conditions in water bodies. In addition to their therapeutic use for the reduction of intestinal phosphate absorption in patients with impaired renal function, the phosphate binding capacity of aluminium and lanthanum also led to the development of materials used for water treatment. Although lanthanum and aluminium share physicochemical similarities and have many common applications, their uptake and kinetics within the human body and living organisms importantly differ from each other which is reflected in a different toxicity profile. Whilst a causal role in the development of neurological pathologies, skeletal lesions, hematopoietic disorders and respiratory effects has unequivocally been demonstrated with increased exposure to aluminium, studies until now have failed to find such a clear association after exposure to lanthanum although caution is warranted. Our review indicates that lanthanum and aluminium have a distinctly different profile with respect to their potential effects on human health. Regular monitoring of both aluminium and lanthanum concentrations in lanthanum-/aluminium-treated water by the responsible authorities is recommended to avoid acute accidental or chronic low level accumulation.
Patrick C. D'Haese; Grant Douglas; Anja Verhulst; Ellen Neven; Geert J. Behets; Benjamin Vervaet; Karin Finsterle; Miquel Lürling; Bryan Spears. Human health risk associated with the management of phosphorus in freshwaters using lanthanum and aluminium. Chemosphere 2018, 220, 286 -299.
AMA StylePatrick C. D'Haese, Grant Douglas, Anja Verhulst, Ellen Neven, Geert J. Behets, Benjamin Vervaet, Karin Finsterle, Miquel Lürling, Bryan Spears. Human health risk associated with the management of phosphorus in freshwaters using lanthanum and aluminium. Chemosphere. 2018; 220 ():286-299.
Chicago/Turabian StylePatrick C. D'Haese; Grant Douglas; Anja Verhulst; Ellen Neven; Geert J. Behets; Benjamin Vervaet; Karin Finsterle; Miquel Lürling; Bryan Spears. 2018. "Human health risk associated with the management of phosphorus in freshwaters using lanthanum and aluminium." Chemosphere 220, no. : 286-299.
Acute kidney injury (AKI) is an underestimated, yet important, risk factor for the development of chronic kidney disease (CKD). Persistence of inflammation after a renal ischemic injury has been observed, both in experimental models and patients, and is thought to be an important mechanisms underlying progression of acute-to-chronic renal injury. Temporary suppression of inflammation immediately after AKI might therefore be a good first-line therapeutic strategy towards a better long term outcome. Male C57Bl/6 J mice (Charles River, 10-12 weeks of age) underwent warm (36 °C body temperature) unilateral ischemia-reperfusion of the kidney for 21 min, after which treatment with intraperitoneal injection of the corticosteroid dexamethasone (10 mg/kg) was initiated for 3 weeks. Both at that time point and after an additional 3 week post-treatment follow up period, fibrosis was quantified by collagen I gene expression and immunostaining, as well as gene expression analysis of fibrosis-related genes Tgfβ, Ccn2 (Ctgf), Pai-1 and Ccn3. Furthermore, inflammation was evaluated by Tnfα gene expression and protein expression of the F4/80 macrophage marker and the α-SMA fibroblast marker. Lastly, renal histopathology was quantified by a morphometric analysis of the tubulointerstitial area. Treatment with dexamethasone attenuated development of fibrosis, as evidenced by reduced collagen I gene expression and immunostaining, in combination with reduced gene expression of the pro-fibrotic Ccn2 and increased expression of the anti-fibrotic Ccn3. The effects of dexamethasone on renal fibrosis persisted during the 3 week follow up period, as evidenced by stagnation of collagen I deposition in the ischemic kidney, in contrast to vehicle-treatment, where progression of fibrosis was observed. However, expression levels of the pro-fibrotic genes re-approached those of vehicle-treated injured kidneys suggesting that the effects of dexamethasone on fibrosis beyond the treatment period are temporary. A short term anti-inflammatory therapy with dexamethasone only transiently attenuates ischemia induced fibrosis. Prolonged or persistent anti-inflammatory treatment seems warranted to achieve long term benefit.
Lies Moonen; Hilde Geryl; Patrick C. D’Haese; Benjamin A. Vervaet. Short-term dexamethasone treatment transiently, but not permanently, attenuates fibrosis after acute-to-chronic kidney injury. BMC Nephrology 2018, 19, 343 .
AMA StyleLies Moonen, Hilde Geryl, Patrick C. D’Haese, Benjamin A. Vervaet. Short-term dexamethasone treatment transiently, but not permanently, attenuates fibrosis after acute-to-chronic kidney injury. BMC Nephrology. 2018; 19 (1):343.
Chicago/Turabian StyleLies Moonen; Hilde Geryl; Patrick C. D’Haese; Benjamin A. Vervaet. 2018. "Short-term dexamethasone treatment transiently, but not permanently, attenuates fibrosis after acute-to-chronic kidney injury." BMC Nephrology 19, no. 1: 343.
Acute kidney injury (AKI), commonly caused by ischemia-reperfusion injury, has far-reaching health consequences. Despite the significant regenerative capacity of proximal tubular epithelium cells (PTCs), repair frequently fails, leading to the development of chronic kidney disease (CKD). In the last decade, it has been repeatedly demonstrated that dysregulation of the cell cycle can cause injured kidneys to progress to CKD. More precisely, severe AKI causes PTCs to arrest in the G1/S or G2/M phase of the cell cycle, leading to maladaptive repair and a fibrotic outcome. The mechanisms causing these arrests are far from known. The arrest might, at least partially, be attributed to DNA damage since activation of the DNA-damage response pathway leads to cell cycle arrest. Alternatively, cytokine signalling via nuclear factor kappa beta (NF-κβ) and p38-mitogen-activated protein kinase (p38-MAPK) pathways, and reactive oxygen species (ROS) can play a role independent of DNA damage. In addition, only a handful of cell cycle regulators (e.g., p53, p21) have been thoroughly studied during renal repair. Still, why and how PTCs decide to arrest their cell cycle and how this arrest can efficiently be overcome remain open and challenging questions. In this review we will discuss the evidence for cell cycle involvement during AKI and development of CKD together with putative therapeutic approaches.
Lies Moonen; Patrick C. D’Haese; Benjamin A. Vervaet. Epithelial Cell Cycle Behaviour in the Injured Kidney. International Journal of Molecular Sciences 2018, 19, 2038 .
AMA StyleLies Moonen, Patrick C. D’Haese, Benjamin A. Vervaet. Epithelial Cell Cycle Behaviour in the Injured Kidney. International Journal of Molecular Sciences. 2018; 19 (7):2038.
Chicago/Turabian StyleLies Moonen; Patrick C. D’Haese; Benjamin A. Vervaet. 2018. "Epithelial Cell Cycle Behaviour in the Injured Kidney." International Journal of Molecular Sciences 19, no. 7: 2038.
Chronic kidney disease (CKD) causes dysregulation of mineral metabolism, vascular calcification and renal osteodystrophy, an entity called 'CKD-Mineral and Bone Disorder' (CKD-MBD). Here we determine whether metformin, an anti-diabetic drug, exerts favorable effects on progressive, severe CKD and concomitant mineral metabolism disturbances. Rats with CKD-MBD, induced by a 0.25% adenine diet for eight weeks, were treated with 200 mg/kg/day metformin or vehicle from one week after CKD induction onward. Severe, stable CKD along with marked hyperphosphatemia and hypocalcemia developed in these rats which led to arterial calcification and high bone turnover disease. Metformin protected from development toward severe CKD. Metformin-treated rats did not develop hyperphosphatemia or hypocalcemia and this prevented the development of vascular calcification and inhibited the progression toward high bone turnover disease. Kidneys of the metformin group showed significantly less cellular infiltration, fibrosis and inflammation. To study a possible direct effect of metformin on the development of vascular calcification, independent of its effect on renal function, metformin (200 mg/kg/day) or vehicle was dosed for ten weeks to rats with warfarin-induced vascular calcification. The drug did not reduce aorta or small vessel calcification in this animal model. Thus, metformin protected against the development of severe CKD and preserved calcium phosphorus homeostasis. As a result of its beneficial impact on renal function, associated comorbidities such as vascular calcification and high bone turnover disease were also prevented.
Ellen Neven; Benjamin Vervaet; Kerstin Brand; Ulrike Gottwald-Hostalek; Britt Opdebeeck; Annelies De Maré; Anja Verhulst; Jean-Daniel Lalau; Said Kamel; Marc E. De Broe; Patrick C. D’Haese. Metformin prevents the development of severe chronic kidney disease and its associated mineral and bone disorder. Kidney International 2018, 94, 102 -113.
AMA StyleEllen Neven, Benjamin Vervaet, Kerstin Brand, Ulrike Gottwald-Hostalek, Britt Opdebeeck, Annelies De Maré, Anja Verhulst, Jean-Daniel Lalau, Said Kamel, Marc E. De Broe, Patrick C. D’Haese. Metformin prevents the development of severe chronic kidney disease and its associated mineral and bone disorder. Kidney International. 2018; 94 (1):102-113.
Chicago/Turabian StyleEllen Neven; Benjamin Vervaet; Kerstin Brand; Ulrike Gottwald-Hostalek; Britt Opdebeeck; Annelies De Maré; Anja Verhulst; Jean-Daniel Lalau; Said Kamel; Marc E. De Broe; Patrick C. D’Haese. 2018. "Metformin prevents the development of severe chronic kidney disease and its associated mineral and bone disorder." Kidney International 94, no. 1: 102-113.