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Scientific Reports Sep 2023Hyperphosphatemia is a major risk for poor prognosis in patients with end-stage renal disease. However, the molecular mechanism behind this link remains elusive. We and...
Hyperphosphatemia is a major risk for poor prognosis in patients with end-stage renal disease. However, the molecular mechanism behind this link remains elusive. We and others have demonstrated that serum phosphorus levels correlate positively with circulating levels of calciprotein particles (CPPs). CPPs are colloidal mineral-protein complexes containing insoluble calcium-phosphate precipitates and have been reported to induce calcification in cultured vascular smooth muscle cells and inflammatory responses in cultured macrophages. Hence, we hypothesize that CPPs may be responsible for disorders associated with hyperphosphatemia. Using hyperphosphatemic miniature pigs receiving hemodialysis, here we show that removal of CPPs from the blood with a newly developed CPP adsorption column improves survival and alleviates complications including coronary artery calcification, vascular endothelial dysfunction, metastatic pulmonary calcification, left ventricular hypertrophy, and chronic inflammation. The present study identifies CPPs as an effective therapeutic target and justifies clinical trials to determine whether the CPP adsorption column may be useful as a medical device for improving clinical outcomes of hemodialysis patients.
Topics: Animals; Swine; Swine, Miniature; Adsorption; Hyperphosphatemia; Prognosis; Renal Dialysis; Calcinosis; Choristoma
PubMed: 37700060
DOI: 10.1038/s41598-023-42273-0 -
Theranostics 2024Vascular calcification (VC) is a life-threatening complication in patients with chronic kidney disease (CKD) caused mainly by hyperphosphatemia. However, the regulation...
Vascular calcification (VC) is a life-threatening complication in patients with chronic kidney disease (CKD) caused mainly by hyperphosphatemia. However, the regulation of VC remains unclear despite extensive research. Although serum- and glucocorticoid-induced kinase 3 (SGK3) regulate the sodium-dependent phosphate cotransporters in the intestine and kidney, its effect on VC in CKD remains unknown. Additionally, type III sodium-dependent phosphate cotransporter-1 (Pit-1) plays a significant role in VC development induced by high phosphate in vascular smooth muscle cells (VSMCs). However, it remains unclear whether SGK3 regulates Pit-1 and how exactly SGK3 promotes VC in CKD via Pit-1 at the molecular level. Thus, we investigated the role of SGK3 in the certified outflow vein of arteriovenous fistulas (AVF) and aortas of uremic mice. In our study, using uremic mice, we observed a significant upregulation of SGK3 and calcium deposition in certified outflow veins of the AVF and aortas, and the increase expression of SGK3 was positively correlated with calcium deposition in uremic aortas. , the downregulation of SGK3 reversed VSMCs calcification and phenotype switching induced by high phosphate. Mechanistically, SGK3 activation enhanced the mRNA transcription of Pit-1 through NF-κB, downregulated the ubiquitin-proteasome mediated degradation of Pit-1 via inhibiting the activity of neural precursor cells expressing developmentally downregulated protein 4 subtype 2 (Nedd4-2), an E3 ubiquitin ligase. Moreover, under high phosphate stimulation, the enhanced phosphate uptake induced by SGK3 activation was independent of the increased protein expression of Pit-1. Our co-immunoprecipitation and kinase assays confirmed that SGK3 interacts with Pit-1 through Thr468 in loop7, leading to enhanced phosphate uptake. Thus, it is justifiable to conclude that SGK3 promotes VC in CKD by enhancing the expression and activities of Pit-1, which indicate that SGK3 could be a therapeutic target for VC in CKD.
Topics: Animals; Humans; Mice; Calcium; Glucocorticoids; Myocytes, Smooth Muscle; Neural Stem Cells; Phosphates; Protein Serine-Threonine Kinases; Renal Insufficiency, Chronic; Sodium; Transcription Factors; Vascular Calcification
PubMed: 38169564
DOI: 10.7150/thno.87317 -
Journal of Molecular and Cellular... Oct 2023Cardiovascular calcification can occur in vascular and valvular structures and is commonly associated with calcium deposition and tissue mineralization leading to...
Cardiovascular calcification can occur in vascular and valvular structures and is commonly associated with calcium deposition and tissue mineralization leading to stiffness and dysfunction. Patients with chronic kidney disease and associated hyperphosphatemia have an elevated risk for coronary artery calcification (CAC) and calcific aortic valve disease (CAVD). However, there is mounting evidence to suggest that the susceptibility and pathobiology of calcification in these two cardiovascular structures may be different, yet clinically they are similarly treated. To better understand diversity in molecular and cellular processes that underlie hyperphosphatemia-induced calcification in vascular and valvular structures, we exposed aortic vascular smooth muscle cells (AVSMCs) and aortic valve interstitial cells (AVICs) to high (2.5 mM) phosphate (Ph) conditions in vitro, and examined cell-specific responses. To further identify hyperphosphatemic-specific responses, parallel studies were performed using osteogenic media (OM) as an alternative calcific stimulus. Consistent with clinical observations made by others, we show that AVSMCs are more susceptible to calcification than AVICs. In addition, bulk RNA-sequencing reveals that AVSMCs and AVICs activate robust ossification-programs in response to high phosphate or OM treatments, however, the signaling pathways, cellular processes and osteogenic-associated markers involved are cell- and treatment-specific. For example, compared to VSMCs, VIC-mediated calcification involves biological processes related to osteo-chondro differentiation and down regulation of 'actin cytoskeleton'-related genes, that are not observed in VSMCs. Furthermore, hyperphosphatemic-induced calcification in AVICs and AVSMCs is independent of P13K signaling, which plays a role in OM-treated cells. Together, this study provides a wealth of information suggesting that the pathogenesis of cardiovascular calcifications is significantly more diverse than previously appreciated.
Topics: Humans; Aortic Valve; Aortic Valve Stenosis; Calcinosis; Muscle, Smooth, Vascular; Hyperphosphatemia; Cells, Cultured; Phosphates; Vascular Calcification
PubMed: 37579636
DOI: 10.1016/j.yjmcc.2023.08.001 -
BMC Genomics Mar 2024Atrial fibrillation (AF) is a prevalent arrhythmic condition resulting in increased stroke risk and is associated with high mortality. Electrolyte imbalance can increase... (Observational Study)
Observational Study
BACKGROUND
Atrial fibrillation (AF) is a prevalent arrhythmic condition resulting in increased stroke risk and is associated with high mortality. Electrolyte imbalance can increase the risk of AF, where the relationship between AF and serum electrolytes remains unclear.
METHODS
A total of 15,792 individuals were included in the observational study, with incident AF ascertainment in the Atherosclerosis Risk in Communities (ARIC) study. The Cox regression models were applied to calculate the hazard ratio (HR) and 95% confidence interval (CI) for AF based on different serum electrolyte levels. Mendelian randomization (MR) analyses were performed to examine the causal association.
RESULTS
In observational study, after a median 19.7 years of follow-up, a total of 2551 developed AF. After full adjustment, participants with serum potassium below the 5th percentile had a higher risk of AF relative to participants in the middle quintile. Serum magnesium was also inversely associated with the risk of AF. An increased incidence of AF was identified in individuals with higher serum phosphate percentiles. Serum calcium levels were not related to AF risk. Moreover, MR analysis indicated that genetically predicted serum electrolyte levels were not causally associated with AF risk. The odds ratio for AF were 0.999 for potassium, 1.044 for magnesium, 0.728 for phosphate, and 0.979 for calcium, respectively.
CONCLUSIONS
Serum electrolyte disorders such as hypokalemia, hypomagnesemia and hyperphosphatemia were associated with an increased risk of AF and may also serve to be prognostic factors. However, the present study did not support serum electrolytes as causal mediators for AF development.
Topics: Humans; Atrial Fibrillation; Risk Factors; Magnesium; Mendelian Randomization Analysis; Calcium; Potassium; Phosphates; Electrolytes; Genome-Wide Association Study
PubMed: 38493091
DOI: 10.1186/s12864-024-10197-2 -
Renal Failure Dec 2024Calciphylaxis (CP) is a serious, potentially life-threatening disease that presents with medial calcification of small-sized vessels and painful ischemic ulcerations....
Calciphylaxis (CP) is a serious, potentially life-threatening disease that presents with medial calcification of small-sized vessels and painful ischemic ulcerations. Although calciphylaxis is frequently seen in patients with end-stage kidney disease on dialysis (calcific uremic arteriolopathy, CUA), there are reported cases of nonuremic calciphylaxis (NUC), which often remain undiagnosed. We conducted a retrospective chart review at our dermatological hospital and evaluated data concerning the epidemiology, comorbidities, medication, laboratory abnormalities, and therapeutic approaches of 60 patients diagnosed with calciphylaxis between 01/2012 and 12/2022. We identified 21 patients diagnosed with NUC and 39 with kidney disease. The predilection sites of skin lesions were the lower legs in 88% ( = 53), followed by the thigh and gluteal regions in 7% ( = 4). Significant differences were identified in comorbidities, such as atrial fibrillation ( and hyperparathyroidism ( accounting for CUA patients. Medication with vitamin K antagonists (, phosphate binders (), and loop diuretics () was found to be associated with the onset of calciphylaxis. Hyperphosphatemia (), increased parathyroid hormone () and triglyceride levels (, hypoalbuminemia ( and decreased hemoglobin values ( in the CUA cohort were significantly different from those in the NUC group. All patients with CUA received systemic medication. In contrast, only 38% ( = 8) of patients with NUC received systemic treatment. Striking discrepancies in the treatment of both cohorts were detected. In particular, NUC remains a disease pattern that is still poorly understood and differs from CUA in several important parameters.
Topics: Humans; Calciphylaxis; Retrospective Studies; Kidney Failure, Chronic; Renal Dialysis; Anticoagulants
PubMed: 38178572
DOI: 10.1080/0886022X.2023.2297566 -
Endocrine Journal Apr 2024Bone secrets the hormone, fibroblast growth factor 23 (FGF23), as an endocrine organ to regulate blood phosphate level. Phosphate is an essential mineral for the human... (Review)
Review
Bone secrets the hormone, fibroblast growth factor 23 (FGF23), as an endocrine organ to regulate blood phosphate level. Phosphate is an essential mineral for the human body, and around 85% of phosphate is present in bone as a constituent of hydroxyapatite, Ca(PO)(OH). Because hypophosphatemia induces rickets/osteomalacia, and hyperphosphatemia results in ectopic calcification, blood phosphate (inorganic form) level must be regulated in a narrow range (2.5 mg/dL to 4.5 me/dL in adults). However, as yet it is unknown how bone senses changes in blood phosphate level, and how bone regulates the production of FGF23. Our previous data indicated that high extracellular phosphate phosphorylates FGF receptor 1 (FGFR1) in an unliganded manner, and its downstream intracellular signaling pathway regulates the expression of GALNT3. Furthermore, the post-translational modification of FGF23 protein via a gene product of GALNT3 is the main regulatory mechanism of enhanced FGF23 production due to high dietary phosphate. Therefore, our research group proposes that FGFR1 works as a phosphate-sensing receptor at least in the regulation of FGF23 production and blood phosphate level, and phosphate behaves as a first messenger. Phosphate is involved in various effects, such as stimulation of parathyroid hormone (PTH) synthesis, vascular calcification, and renal dysfunction. Several of these responses to phosphate are considered as phosphate toxicity. However, it is not clear whether FGFR1 is involved in these responses to phosphate. The elucidation of phosphate-sensing mechanisms may lead to the identification of treatment strategies for patients with abnormal phosphate metabolism.
Topics: Fibroblast Growth Factor-23; Humans; Phosphates; Fibroblast Growth Factors; Animals; Receptor, Fibroblast Growth Factor, Type 1; Signal Transduction; Bone and Bones; N-Acetylgalactosaminyltransferases; Hyperphosphatemia; Polypeptide N-acetylgalactosaminyltransferase
PubMed: 38556320
DOI: 10.1507/endocrj.EJ24-0082 -
SAGE Open Medical Case Reports 2023Pseudohypoparathyroidism is a terminology used to describe a group of metabolic disorders characterized by parathyroid hormone resistance. Patients with...
Pseudohypoparathyroidism is a terminology used to describe a group of metabolic disorders characterized by parathyroid hormone resistance. Patients with pseudohypoparathyroidism have hypocalcemia, hyperphosphatemia, and elevated serum parathyroid hormone. This methylation defect leads to signaling abnormalities in the parathyroid hormone and parathyroid hormone-related peptide receptor. We present a 40-year-old African American male who was referred to our endocrinology clinic for hypocalcemia. On physical examination, his body mass index was 34.3 kg/m and he was found to have a round face, and several subcutaneous nodules on his scalp, hands, and legs. Laboratory findings revealed hypocalcemia, hyperphosphatemia, and elevated levels of intact parathyroid hormone and thyroid stimulating hormone (TSH). His hand X-ray showed brachydactyly of all metacarpal bones, and soft tissue calcifications. Brain CT indicated dense calcifications in the subcortical region, bilateral basal ganglia, bilateral thalami, bilateral cerebellum and vermis, and soft tissue calcifications in the scalp. The "inactivating parathyroid hormone/parathyroid hormone-related peptide signaling disorder" diagnostic approach suggested by the Euro pseudohypoparathyroidism network was applied to the patient, who was diagnosed with parathyroid hormone signaling disorder. Compared to the old pseudohypoparathyroidism classification and the 2018 Pseudohypoparathyroidism International Consensus Statement Report, the inactivating parathyroid hormone/parathyroid hormone-related peptide signaling disorder cluster classification appears to be more flexible, and easier to use. It also accommodates future inclusion of genetic mutations associated with hormonal signaling disorders. Adoption of the inactivating parathyroid hormone/parathyroid hormone-related peptide signaling disorder classification remains limited, and further larger studies are needed to compare the three approaches.
PubMed: 37860280
DOI: 10.1177/2050313X231205776 -
Asian Biomedicine : Research, Reviews... Feb 2024Dietary protein restriction has been considered to be a nutritional-related strategy to reduce risk for end-stage kidney disease among patients with... (Review)
Review
Dietary protein restriction has been considered to be a nutritional-related strategy to reduce risk for end-stage kidney disease among patients with non-dialysis-dependent chronic kidney disease (CKD). However, there is insufficient evidence to recommend a particular type of protein to slow down the CKD progression. Recently, various plant-based diets could demonstrate some additional benefits such as a blood pressure-lowering effect, a reduction of metabolic acidosis as well as hyperphosphatemia, and gut-derived uremic toxins. Furthermore, the former concerns about the risk of undernutrition and hyperkalemia observed with plant-based diets may be inconsistent in real clinical practice. In this review, we summarize the current evidence of the proposed pleiotropic effects of plant-based diets and their associations with clinical outcomes among pre-dialysis CKD patients.
PubMed: 38515633
DOI: 10.2478/abm-2024-0002 -
Clinical Cancer Research : An Official... Oct 2023On September 30, 2022, the FDA granted accelerated approval to futibatinib for the treatment of adult patients with previously treated, unresectable, locally advanced or...
FDA Approval Summary: Futibatinib for Unresectable Advanced or Metastatic, Chemotherapy Refractory Intrahepatic Cholangiocarcinoma with FGFR2 Fusions or Other Rearrangements.
On September 30, 2022, the FDA granted accelerated approval to futibatinib for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions or other rearrangements. Approval was based on Study TAS-120-101, a multicenter open-label, single-arm trial. Patients received futibatinib 20-mg orally once daily. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) as determined by an independent review committee (IRC) according to RECIST v1.1. ORR was 42% (95% confidence interval, 32%-52%). Median DoR was 9.7 months. Adverse reactions occurring in ≥30% patients were nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry mouth, alopecia, stomatitis, and abdominal pain. The most common laboratory abnormalities (≥50%) were increased phosphate, increased creatinine, decreased hemoglobin, and increased glucose. Ocular toxicity (including dry eye, keratitis, and retinal epithelial detachment) and hyperphosphatemia are important risks of futibatinib, which are listed under Warnings and Precautions. This article summarizes the FDA's thought process and data supporting the approval of futibatinib.
Topics: Adult; Humans; Pyrimidines; Cholangiocarcinoma; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Drug Approval; Receptor, Fibroblast Growth Factor, Type 2; Pyrazoles; Pyrroles
PubMed: 37289037
DOI: 10.1158/1078-0432.CCR-23-1042 -
PeerJ 2023There remain controversies over the conclusion of different serum phosphate levels as prognostic predictors of sepsis patients. As such, this study investigated the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
There remain controversies over the conclusion of different serum phosphate levels as prognostic predictors of sepsis patients. As such, this study investigated the association between different serum phosphate and the prognosis of sepsis.
METHODS
Data from PubMed, Embase, Cochrane Library, and Web of Science were systematically retrieved from the inception of databases to June 1, 2023 and independently screened and extracted by two authors. Binary variables in the study were estimated as relative risk ratio (RR) and 95% confidence interval (CI), and continuous variables were estimated as mean and standard deviation. The Newcastle-Ottawa Scale (NOS) was employed to evaluate the quality of the included studies, and subgroup analysis and sensitivity analysis were performed for all outcomes to explore the sources of heterogeneity.
RESULTS
Ten studies were included in this study including 38,320 patients with sepsis or septic shock. Against normal serum phosphate levels, a high serum phosphate level was associated with an elevated all-cause mortality risk (RR = 1.46; 95% CI [1.22-1.74]; = 0.000) and prolonged Intensive Care Unit (ICU) length of stay (LOS) (WMD = 0.63; 95% CI [0.27-0.98]; = 0.001). However, there was no significant difference in the in-hospital LOS (WMD = 0.22; 95% CI [-0.61-1.05]; = 0.609). A low serum phosphate level was not significantly associated with the all-cause mortality risk (RR = 0.97; 95% CI [0.86-1.09]; = 0.588), ICU LOS (WMD = -0.23; 95% CI [-0.75-0.29]; = 0.394) and in-hospital LOS (WMD = -0.62; 95% CI [-1.72-0.49]; = 0.274).
CONCLUSION
Sepsis patients with high serum phosphate levels before therapeutic interventions were associated with a significant increase in the all-cause mortality risk, prolonged ICU LOS, and no significant difference in in-hospital LOS. Sepsis patients with low serum phosphate levels before interventions may have a reduced risk of all-cause mortality, shorter ICU LOS, and in-hospital LOS, but the results were not statistically significant.
Topics: Humans; Prognosis; Sepsis; Shock, Septic; Intensive Care Units; Phosphates
PubMed: 37849826
DOI: 10.7717/peerj.16241