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Journal of Visualized Experiments : JoVE Jul 2023Hypoparathyroidism (HypoPT) is a rare disease involving the parathyroid glands that is characterized by a reduced secretion or potency of the parathyroid hormone (PTH),...
Hypoparathyroidism (HypoPT) is a rare disease involving the parathyroid glands that is characterized by a reduced secretion or potency of the parathyroid hormone (PTH), which leads to high serum phosphorus levels and low serum calcium levels. HypoPT most commonly results from accidental damage to the glands or their removal during thyroid or other anterior neck surgery. Parathyroid/thyroid surgery has become more common in recent years, with a corresponding rise in the occurrence of HypoPT as a postoperative complication. There is a critical need for a HypoPT animal model to better understand the mechanisms underlying the effects of HypoPT on mineral ion homeostasis and to verify the therapeutic effectiveness of novel treatments. Here, a technique is reported to create acquired HypoPT in male rats by performing parathyroidectomy (PTX) using carbon nanoparticles. The rat model shows great promise over the mouse models of hypoparathyroidism. Importantly, the human PTH receptor binding region has an 84.2% sequence similarity with that of the rat, which is higher than the 73.7% similarity shared with mice. Moreover, the effects of estrogen, which can affect the PTH/PTHrP receptor signaling pathway, have not been fully investigated in male rats. Carbon nanoparticles are lymphatic tracers that stain the thyroid lymph nodes black without affecting their function, but they do not stain the parathyroid glands, which makes them easy to identify and remove. In this study, serum PTH levels were undetectable after PTX, and this resulted in significant hypocalcemia and hyperphosphatemia. Thus, the clinical state of postoperative HypoPT can be remarkably represented in the rat model. Carbon-nanoparticle-assisted PTX can, therefore, serve as an extraordinarily effective and readily implementable model for studying the pathogenesis, treatment, and prognosis of HypoPT.
Topics: Animals; Male; Rats; Calcium; Carbon; Hypoparathyroidism; Nanoparticles; Parathyroid Hormone; Parathyroidectomy
PubMed: 37522721
DOI: 10.3791/64611 -
Biology Feb 2024The primary cause of worldwide mortality and morbidity stems from complications in the cardiovascular system resulting from accelerated atherosclerosis and arterial... (Review)
Review
The primary cause of worldwide mortality and morbidity stems from complications in the cardiovascular system resulting from accelerated atherosclerosis and arterial stiffening. Frequently, both pathologies are associated with the pathological calcification of cardiovascular structures, present in areas such as cardiac valves or blood vessels (vascular calcification). The accumulation of hydroxyapatite, the predominant form of calcium phosphate crystals, is a distinctive feature of vascular calcification. This phenomenon is commonly observed as a result of aging and is also linked to various diseases such as diabetes, chronic kidney disease, and several genetic disorders. A substantial body of evidence indicates that vascular calcification involves two primary processes: a passive process and an active process. The physicochemical process of hydroxyapatite formation and deposition (a passive process) is influenced significantly by hyperphosphatemia. However, the active synthesis of calcification inhibitors, including proteins and low-molecular-weight inhibitors such as pyrophosphate, is crucial. Excessive calcification occurs when there is a loss of function in enzymes and transporters responsible for extracellular pyrophosphate metabolism. Current in vivo treatments to prevent calcification involve addressing hyperphosphatemia with phosphate binders and implementing strategies to enhance the availability of pyrophosphate.
PubMed: 38392329
DOI: 10.3390/biology13020111 -
American Journal of Kidney Diseases :... Jul 2023Patients with chronic kidney disease (CKD), hyperkalemia (serum potassium [sK]>5.0 mEq/L), and hyperphosphatemia experience poor clinical outcomes. Patiromer, a...
RATIONALE & OBJECTIVE
Patients with chronic kidney disease (CKD), hyperkalemia (serum potassium [sK]>5.0 mEq/L), and hyperphosphatemia experience poor clinical outcomes. Patiromer, a potassium binder that uses calcium as the exchange ion, may also reduce serum phosphorus (sP). We characterized the effect of patiromer on sP in patients with CKD, hyperkalemia, and hyperphosphatemia.
STUDY DESIGN
A post hoc pooled analysis of individual-level data from the AMETHYST-DN, OPAL-HK, and TOURMALINE trials of patiromer.
SETTING & PARTICIPANTS
Patients with CKD and hyperkalemia.
EXPOSURE
Patients treated with patiromer (8.4-33.6 g/day).
OUTCOME
Mean changes from baseline in sP, sK, serum calcium (sCa2), and serum magnesium (sMg2) after 2 and 4 weeks of treatment.
ANALYTICAL APPROACH
Descriptive statistics to summarize pooled data on the study outcomes from the 3 studies.
RESULTS
We included 578 patients in the analysis. Of these participants, 86 patients (14.9%) had baseline hyperphosphatemia of whom 75.6% (65 of 86) had CKD stage 4/5 and 31.1% (153 of 492) with sP≤4.5mg/dL had CKD stage 4/5. Among the patients with elevated sP and sKat baseline, the mean±SD reduction in sP and sKafter 4 weeks of patiromer treatment was-0.62±1.09mg/dL and-0.71± 0.51 mEq/L, respectively. Additionally, the mean±SD reduction in sMgin these patients was -0.25±0.23mg/dL while sCaremained unchanged. Both sMgand sCaremained within the normal range. Patiromer was generally well tolerated, and no serious adverse events were considered related to patiromer.
LIMITATIONS
These were post hoc analyses, no placebo comparison was performed due to the design of the original studies, and the follow-up period was limited to 4 weeks.
CONCLUSIONS
Reductions in sP and sKto the normal range were observed after 2 weeks of patiromer treatment, and the reduction was sustained during 4 weeks of treatment among patients with non-dialysis-dependent CKD, hyperkalemia, and hyperphosphatemia. Future controlled trials are needed to establish if patiromer is useful to reduce both sKand sP in hyperkalemic patients with CKD and hyperphosphatemia.
Topics: Humans; Hyperkalemia; Hyperphosphatemia; Calcium; Potassium; Renal Insufficiency, Chronic; Phosphorus
PubMed: 36965827
DOI: 10.1053/j.ajkd.2023.01.444 -
Therapeutic Apheresis and Dialysis :... Oct 2023The effects of tenapanor in reducing serum phosphorus in hemodialysis patients with hyperphosphatemia are uncertain and no relevant meta-analysis has been conducted. We... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The effects of tenapanor in reducing serum phosphorus in hemodialysis patients with hyperphosphatemia are uncertain and no relevant meta-analysis has been conducted. We performed a meta-analysis of randomized placebo-controlled trials to evaluate the efficacy and safety of tenapanor.
METHODS
All randomized controlled trials of tenapanor were searched up to 1 August 2022. The primary endpoint was the change in serum phosphorus level from baseline with tenapanor and placebo. Data on drug-related adverse events (AEs), gastrointestinal AEs and diarrhea were collected to determine the safety of tenapanor.
RESULTS
There were 533 patients throughout five trials that were eligible. Tenapanor significantly lowered blood phosphorus level by 1.79 mg/dl in the mean difference than the placebo. Diarrhea, gastrointestinal AEs, and drug-related AEs were more severe than placebo.
CONCLUSIONS
This meta-analysis showed that although drug side effects were common, tenapanor significantly reduced serum phosphorus level in hemodialysis patients.
Topics: Humans; Hyperphosphatemia; Double-Blind Method; Renal Dialysis; Diarrhea; Phosphorus; Randomized Controlled Trials as Topic
PubMed: 37349983
DOI: 10.1111/1744-9987.14028 -
Arteriosclerosis, Thrombosis, and... Mar 2024Hyperphosphatemia is a common feature in patients with impaired kidney function and is associated with increased risk of cardiovascular disease. This phenomenon extends... (Review)
Review
Hyperphosphatemia is a common feature in patients with impaired kidney function and is associated with increased risk of cardiovascular disease. This phenomenon extends to the general population, whereby elevations of serum phosphate within the normal range increase risk; however, the mechanism by which this occurs is multifaceted, and many aspects are poorly understood. Less than 1% of total body phosphate is found in the circulation and extracellular space, and its regulation involves multiple organ cross talk and hormones to coordinate absorption from the small intestine and excretion by the kidneys. For phosphate to be regulated, it must be sensed. While mostly enigmatic, various phosphate sensors have been elucidated in recent years. Phosphate in the circulation can be buffered, either through regulated exchange between extracellular and cellular spaces or through chelation by circulating proteins (ie, fetuin-A) to form calciprotein particles, which in themselves serve a function for bulk mineral transport and signaling. Either through direct signaling or through mediators like hormones, calciprotein particles, or calcifying extracellular vesicles, phosphate can induce various cardiovascular disease pathologies: most notably, ectopic cardiovascular calcification but also left ventricular hypertrophy, as well as bone and kidney diseases, which then propagate phosphate dysregulation further. Therapies targeting phosphate have mostly focused on intestinal binding, of which appreciation and understanding of paracellular transport has greatly advanced the field. However, pharmacotherapies that target cardiovascular consequences of phosphate directly, such as vascular calcification, are still an area of great unmet medical need.
Topics: Humans; Phosphates; Cardiovascular Diseases; Hyperphosphatemia; Vascular Calcification; Hormones; Renal Insufficiency, Chronic
PubMed: 38205639
DOI: 10.1161/ATVBAHA.123.319198 -
International Journal of Molecular... Apr 2024To maintain an optimal body content of phosphorus throughout postnatal life, variable phosphate absorption from food must be finely matched with urinary excretion. This... (Review)
Review
To maintain an optimal body content of phosphorus throughout postnatal life, variable phosphate absorption from food must be finely matched with urinary excretion. This amazing feat is accomplished through synchronised phosphate transport by myriads of ciliated cells lining the renal proximal tubules. These respond in real time to changes in phosphate and composition of the renal filtrate and to hormonal instructions. How they do this has stimulated decades of research. New analytical techniques, coupled with incredible advances in computer technology, have opened new avenues for investigation at a sub-cellular level. There has been a surge of research into different aspects of the process. These have verified long-held beliefs and are also dramatically extending our vision of the intense, integrated, intracellular activity which mediates phosphate absorption. Already, some have indicated new approaches for pharmacological intervention to regulate phosphate in common conditions, including chronic renal failure and osteoporosis, as well as rare inherited biochemical disorders. It is a rapidly evolving field. The aim here is to provide an overview of our current knowledge, to show where it is leading, and where there are uncertainties. Hopefully, this will raise questions and stimulate new ideas for further research.
Topics: Humans; Phosphates; Animals; Renal Reabsorption; Kidney; Kidney Tubules, Proximal
PubMed: 38731904
DOI: 10.3390/ijms25094684 -
Journal of Atherosclerosis and... Jan 2024Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Both traditional and CKD-related factors are associated with... (Review)
Review
Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Both traditional and CKD-related factors are associated with CVD in CKD patients. Traditional factors that play an important role in the atherosclerotic process directly contribute to a higher risk of coronary artery disease in patients with early-stage CKD. Among CKD-related factors, CKD-mineral and bone disorder plays a critical role in the pathomechanism of nonatherosclerotic diseases, which increases the risk of cardiovascular morbidity and mortality in patients with advanced CKD. Higher serum phosphate levels were significantly associated with cardiovascular events and all-cause mortality in patients with or without CKD. An increased phosphate load, directly and indirectly, promotes arterial medial calcification and left ventricular hypertrophy, both of which predispose patients to coronary artery disease. Calciprotein particles that form in a hyperphosphatemic state promote the transformation of vascular smooth muscle cells (VSMCs) into osteoblastic cells, thereby providing a scaffold for medial calcification in the artery. Increases in fibroblast growth factor-23 and disturbed vitamin D metabolism induced by an excessive phosphate load play a significant role in the development of cardiomyocyte hypertrophy and cardiac fibrosis. Recently, hyperphosphatemia was reported to promote de novo cholesterol synthesis in VSMCs and macrophages, which is likely to contribute to statin resistance in patients with end-stage kidney disease. This review outlines the association between increased phosphate load and coronary artery disease in patients with CKD.
Topics: Humans; Phosphates; Coronary Artery Disease; Renal Insufficiency, Chronic; Kidney Failure, Chronic; Hyperphosphatemia; Cardiovascular Diseases; Vascular Calcification
PubMed: 37766573
DOI: 10.5551/jat.RV22012 -
Archives of Osteoporosis Nov 2023Denosumab can improve bone health in advanced kidney disease (CKD) but is associated with hypocalcemia. We created a clinical care pathway focused on the safe provision...
UNLABELLED
Denosumab can improve bone health in advanced kidney disease (CKD) but is associated with hypocalcemia. We created a clinical care pathway focused on the safe provision of denosumab in advanced CKD that reduced the risk of hypocalcemia by 37% at our hospital. Similar pathways could be adopted and tested in other centers.
PURPOSE
There is an increased risk of hypocalcemia with denosumab in advanced chronic kidney disease (CKD). We aimed to reduce the proportion of patients with advanced CKD who experienced denosumab-induced hypocalcemia at our center.
METHODS
We conducted a quality improvement (QI) project of patients with CKD stage 3b or less (i.e., estimated glomerular filtration rate <45 mL/min/1.73m including dialysis) who were part of the Osteoporosis and Bone Disease Program at St. Joseph's Health Care London (Canada) between December 2020 and January 2023. Our intervention was a clinical care pathway which optimized CKD mineral and bone disorder (CKD-MBD) and 25-hydroxyvitamin levels; provided calcium and vitamin D prophylaxis; promoted multidisciplinary communication between bone and kidney specialists; and carefully monitored calcium post-denosumab injection. Our primary outcome measure was the proportion of patients with hypocalcemia (defined by albumin-corrected serum calcium <1.9mmol/L) at 60 days. Process measures included the appropriate provision of calcium and vitamin D prophylaxis. Balance measures included the development of hypercalcemia and hyperphosphatemia following prophylaxis. We used plan-do-see-act cycles to study four tests of change and presented results using descriptive statistics and run charts.
RESULTS
There were 6 patients with advanced CKD treated with denosumab prior to the implementation of our care pathway (March 2015-October 2020; 83% receiving dialysis). At the time of their denosumab injection, 83% were using 500-1000 mg of calcium, and 83% used 1000-2000 IU of vitamin D. Fifty percent developed denosumab-induced hypocalcemia. Following the implementation of our care pathway, 15 patients (40% receiving dialysis) were treated with denosumab. Ninety-three percent received calcium at a daily dose of 350 to 2250 mg and 87% received 1000-2000 IU of vitamin D. Thirteen percent developed denosumab-induced hypocalcemia. There was no hypercalcemia or hyperphosphatemia.
CONCLUSIONS
A clinical care pathway focused on the safe provision of denosumab in advanced CKD reduced the risk of hypocalcemia in patients treated in our hospital. Similar pathways could be adopted and tested in other centers.
Topics: Humans; Hypocalcemia; Denosumab; Calcium; Bone Density Conservation Agents; Hyperphosphatemia; Quality Improvement; Renal Insufficiency, Chronic; Cholecalciferol; Hypercalcemia
PubMed: 37985504
DOI: 10.1007/s11657-023-01341-8 -
Journal of Renal Nutrition : the... Nov 2023Phosphorus is a vital nutrient, but disturbances in phosphorus homeostasis are central to chronic kidney disease-mineral and bone disorder. To minimize disturbances,... (Review)
Review
Phosphorus is a vital nutrient, but disturbances in phosphorus homeostasis are central to chronic kidney disease-mineral and bone disorder. To minimize disturbances, traditional dietary guidance focused on a numerical phosphorus target leading to the exclusion of many healthy foods and implementation challenges. Contemporary phosphorus guidance focuses on dietary source, avoiding additives, and emphasizing low-phosphorus bioaccessibility foods, leading to a more liberal approach. Additional work is needed to demonstrate the efficacy of these contemporary approaches and understand the influence of specific foods, processing, and cooking methods. Unfortunately, patient education using traditional and contemporary strategies may give mixed messages, particularly related to plant-based foods. Thus, greater clarity on the effects of specific foods and dietary patterns may improve phosphorus education. This review aims to discuss the evolution of dietary phosphorus management while highlighting areas for future research that can help move the field toward stronger evidence-based guidance to prevent and treat hyperphosphatemia.
Topics: Humans; Phosphorus; Phosphorus, Dietary; Renal Insufficiency, Chronic; Hyperphosphatemia; Diet
PubMed: 37343779
DOI: 10.1053/j.jrn.2023.05.004 -
Molecular Genetics and Metabolism Nov 2023Biallelic pathogenic variants in PGAP3 cause a rare glycosylphosphatidyl-inositol biogenesis disorder, PGAP3-CDG. This multisystem condition presents with a... (Review)
Review
Biallelic pathogenic variants in PGAP3 cause a rare glycosylphosphatidyl-inositol biogenesis disorder, PGAP3-CDG. This multisystem condition presents with a predominantly neurological phenotype, including developmental delay, intellectual disability, seizures, and hyperphosphatemia. Here, we summarized the phenotype of sixty-five individuals including six unreported individuals from our CDG natural history study with a confirmed PGAP3-CDG diagnosis. Common additional features found in this disorder included brain malformations, behavioral abnormalities, cleft palate, and characteristic facial features. This report aims to review the genetic and metabolic findings and characterize the disease's phenotype while highlighting the necessary clinical approach to improve the management of this rare CDG.
Topics: Humans; Abnormalities, Multiple; Glycosylation; Phenotype; Intellectual Disability; Seizures; Congenital Disorders of Glycosylation; Carboxylic Ester Hydrolases; Receptors, Cell Surface
PubMed: 37647829
DOI: 10.1016/j.ymgme.2023.107688