SGK3 promotes vascular calcification via Pit-1 in chronic kidney disease.

Rationale: 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. Methods and Results: 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. In vitro, 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 in vitro kinase assays confirmed that SGK3 interacts with Pit-1 through Thr468 in loop7, leading to enhanced phosphate uptake. Conclusion: 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.

Acute hypernatremia and hypocalcemia after oral sodium phosphate administration to a dog.

A 15-year-old male neutered mixed breed dog weighing 28 kg presented to a referral center after developing severe tremors and altered mentation. There was hypocalcemia and hypernatremia after oral administration of sodium phosphate as a bowel cleansing agent in preparation for colonoscopy. The dog was treated intravenously with low sodium fluids and calcium gluconate. Neurologic status and electrolyte derangements normalized over the next 12 hours. Oral administration of sodium phosphate appeared to cause clinical electrolyte derangements in this dog.

Incidence and predictors of hypophosphataemia after ferric carboxymaltose use-A 3-year experience from a single institution in Singapore.

Ferric carboxymaltose (FCM) administration helps reduce transfusion requirements in the perioperative situation, which improves patient outcomes and reduces healthcare costs. However, there is increasing evidence of hypophosphataemia after FCM use. We aim to determine the incidence of hypophosphataemia after FCM administration and elucidate potential biochemical factors associated with the development of subsequent hypophosphataemia. A retrospective review of anonymised data of all FCM administrations in a single institution was conducted from August 2018 to August 2021. Each unique FCM dose administered was examined to assess its effect on Hb and serum phosphate levels within the subsequent 28 days from each FCM administration. Phosphate levels were repeatedly measured within the 28-day interval and the lowest phosphate level within that period was determined. Patients' serum phosphate levels within 28 days of FCM administration were compared against normal serum phosphate levels within 2 weeks before FCM administration. The odds ratios of various pre-FCM serum markers were calculated to elucidate potential biochemical predictors of post-FCM hypophosphataemia. In 3 years, a total of 1296 doses of FCM were administered to 1069 patients. The mean improvement in Hb was 2.45 g/dL (SD = 1.94) within 28 days of FCM administration, with the mean time taken to peak Hb levels being 6.3 days (SD = 8.63), which is earlier than expected, but was observed in this study and hence reported. The incidence of hypophosphataemia <0.8 mmol/L was 22.7% (n = 186), and <0.4 mmol/L was 1.6% (n = 9). This figure is lower than the numbers reported in previously published meta-analyses given that routine checks of serum phosphate levels were not conducted initially and hence could possibly be higher. The odds of developing hypophosphataemia (<0.8 mmol/L) were 27.7 (CI: 17.3-44.2, p < 0.0001) if baseline serum phosphate was less than 1 mmol/L. The odds of developing hypophosphataemia (<0.8 mmol/L) were 1.3 (CI: 1.08-1.59, p < 0.01) if the change in Hb levels observed after FCM administration were more than 4 g/dL. Hypophosphataemia after FCM administration is significant and FCM should be used by clinicians with caution.

A comparative study between the possible protective role of melatonin versus its combination with adipose derived-mesenchymal stem cells on experimentally induced diabetic retinopathy in adult male albino rats (Histological and immunohistochemical study).

Diabetes mellitus is a metabolic disorder that can cause numerous ocular issues as well as long-term effects. In our study, we evaluate the effect of melatonin on the diabetic retinal alterations in male albino rats to the effect of melatonin combined with stem cells. 50 adult male rats were equally divided into four groups control, diabetic, melatonin, and melatonin plus stem cells. STZ, 65 mg/kg in phosphate buffered was administered intraperitoneally as a bolus to diabetic group of rats. After inducing diabetes, melatonin (10 mg/kg b.wt./day) was administered orally to the melatonin group for 8 weeks. The stem cell and melatonin group got the same dosage of melatonin as the prior group. They received an intravenous injection of (3?×?106 cell) adipose-derived MSC suspended in phosphate-buffered saline at same time of melatonin ingestion. Animals from all groups had their fundics examined. Following the injection of stem cells, samples of rat retina were collected for light and electron microscopy analyses. H&E and immunohistochemically stained sections revealed a slight improvement in group (III). At the same time, group (IV) results were comparable to those of the control group, which was supported by the findings of an electron microscope. Neovascularization was visible on fundus examination in group (II), whereas it was less noticeable in group (III) and group IV. Melatonin mildly improved the histological structure of the retina in diabetic rats, and when it was combined with adipose-derived MSC, it considerably improved the diabetic alterations.

[Hypophosphatemia after injectable iron treatments in adults: Comparison between ferric carboxymaltose and iron sucrose]. / Hypophosphorémie après traitement par fer injectable chez l'adulte : comparaison entre le carboxymaltose ferrique et l'hydroxyde ferrique-saccharose.

Hypophosphatemia is a recognized side effect of treatment of iron deficiency anemias with injectable iron. We analyzed 35 clinical trials that used ferric carboxymaltose (FCM) or iron sucrose (IS). Hypophosphatemia prevalence ranged from 0 to 91.7%. FCM-induced a significant (P<0.001) greater hypophosphatemia prevalence and phosphatemia decrease than IS (52.0% [95% CI: 42.2-61.8%] vs. 7.7% [95% CI: -2.8 to 18.2%] and -1.12mmol/L [95% CI: -1.36 to -0.89mmol/L] vs. -0.13mmol/L [95% CI: -0.59 to 0.32mmol/L]). FCM-induced hypophosphatemia was dose-dependent. The nadir of hypophosphatemia was reached in almost all studies after 7 and 14days. Hypophosphatemia persisted at the end of the study in 53.8% of the reported studies that used FCM and lasted up to 6months. FCM-induced an increase in intact circulating fibroblast growth factor 23 and in renal phosphorus excretion while serum 1-25 dihydroxyvitamin D was decreased. Risk factors for hypophosphatemia after FCM therapy were low basal circulating phosphate or ferritin, low body weight, high glomerular filtration rate, serum parathyroid hormone or hemoglobin and age, whereas renal insufficiency was associated with a lower risk. In conclusion, hypophosphatemia is common after treatment with injectable iron, FCM being associated with a higher risk than IS and with disorders of phosphocalcium metabolism. Monitoring of blood phosphate and 1-25 dihydroxyvitamin D could be considered during FCM therapy.

Inhibition of mitochondrial phosphate carrier prevents high phosphate-induced superoxide generation and vascular calcification.

Vascular calcification is a serious complication of hyperphosphatemia that causes cardiovascular morbidity and mortality. Previous studies have reported that plasmalemmal phosphate (Pi) transporters, such as PiT-1/2, mediate depolarization, Ca2+ influx, oxidative stress, and calcific changes in vascular smooth muscle cells (VSMCs). However, the pathogenic mechanism of mitochondrial Pi uptake in vascular calcification associated with hyperphosphatemia has not been elucidated. We demonstrated that the phosphate carrier (PiC) is the dominant mitochondrial Pi transporter responsible for high Pi-induced superoxide generation, osteogenic gene upregulation, and calcific changes in primary VSMCs isolated from rat aortas. Notably, acute incubation with high Pi markedly increased the protein abundance of PiC via ERK1/2- and mTOR-dependent translational upregulation. Genetic suppression of PiC prevented Pi-induced ERK1/2 activation, superoxide production, osteogenic differentiation, and vascular calcification of VSMCs in vitro and aortic rings ex vivo. Pharmacological inhibition of mitochondrial Pi transport using butyl malonate (BMA) or mersalyl abolished all pathologic changes involved in high Pi-induced vascular calcification. BMA or mersalyl also effectively prevented osteogenic gene upregulation and calcification of aortas from 5/6 subtotal nephrectomized mice fed a high-Pi diet. Our results suggest that mitochondrial Pi uptake via PiC is a critical molecular mechanism mediating mitochondrial superoxide generation and pathogenic calcific changes, which could be a novel therapeutic target for treating vascular calcification associated with hyperphosphatemia.

Phosphate NIMA-Related Kinase 2-Dependent Epigenetic Pathways in Dorsal Root Ganglion Neurons Mediates Paclitaxel-Induced Neuropathic Pain.

BACKGROUND: The microtubule-stabilizing drug paclitaxel (PTX) is an important chemotherapeutic agent for cancer treatment and causes peripheral neuropathy as a common side effect that substantially impacts the functional status and quality of life of patients. The mechanistic role for NIMA-related kinase 2 (NEK2) in the progression of PTX-induced neuropathic pain has not been established. METHODS: Adult male Sprague-Dawley rats intraperitoneally received PTX to induce neuropathic pain. The protein expression levels in the dorsal root ganglion (DRG) of animals were measured by biochemical analyses. Nociceptive behaviors were evaluated by von Frey tests and hot plate tests. RESULTS: PTX increased phosphorylation of the important microtubule dynamics regulator NEK2 in DRG neurons and induced profound neuropathic allodynia. PTX-activated phosphorylated NEK2 (pNEK2) increased jumonji domain-containing 3 (JMJD3) protein, a histone demethylase protein, to specifically catalyze the demethylation of the repressive histone mark H3 lysine 27 trimethylation (H3K27me3) at the Trpv1 gene, thereby enhancing transient receptor potential vanilloid subtype-1 (TRPV1) expression in DRG neurons. Moreover, the pNEK2-dependent PTX response program is regulated by enhancing p90 ribosomal S6 kinase 2 (RSK2) phosphorylation. Conversely, intrathecal injections of kaempferol (a selective RSK2 activation antagonist), NCL 00017509 (a selective NEK2 inhibitor), NEK2-targeted siRNA, GSK-J4 (a selective JMJD3 inhibitor), or capsazepine (an antagonist of TRPV1 receptor) into PTX-treated rats reversed neuropathic allodynia and restored silencing of the Trpv1 gene, suggesting the hierarchy and interaction among phosphorylated RSK2 (pRSK2), pNEK2, JMJD3, H3K27me3, and TRPV1 in the DRG neurons in PTX-induced neuropathic pain. CONCLUSIONS: pRSK2/JMJD3/H3K27me3/TRPV1 signaling in the DRG neurons plays as a key regulator for PTX therapeutic approaches.

Nidogen-2 is a Novel Endogenous Ligand of LGR4 to Inhibit Vascular Calcification.

BACKGROUND: Vascular calcification is closely related to the all-cause mortality of cardiovascular events. Basement membrane protein nidogen-2 is a key component of the vascular extracellular matrix microenvironment and we recently found it is pivotal for the maintenance of contractile phenotype in vascular smooth muscle cells (VSMCs). However, whether nidogen-2 is involved in VSMCs osteochondrogenic transition and vascular calcification remains unclear. METHODS: VSMCs was treated with high-phosphate to study VSMC calcification in vitro. Three different mice models (5/6 nephrectomy-induced chronic renal failure, cholecalciferol-overload, and periadventitially administered with CaCl2) were used to study vascular calcification in vivo. Membrane protein interactome, coimmunoprecipitation, flow cytometric binding assay, surface plasmon resonance, G protein signaling, VSMCs calcium assays were performed to clarify the phenotype and elucidate the molecular mechanisms. RESULTS: Nidogen-2 protein levels were significantly reduced in calcified VSMCs and aortas from mice in different vascular calcification model. Nidogen-2 deficiency exacerbated high-phosphate-induced VSMC calcification, whereas the addition of purified nidogen-2 protein markedly alleviated VSMC calcification in vitro. Nidogen-2-/- mice exhibited aggravated aorta calcification compared to wild-type (WT) mice in response to 5/6 nephrectomy, cholecalciferol-overload, and CaCl2 administration. Further unbiased coimmunoprecipitation and interactome analysis of purified nidogen-2 and membrane protein in VSMCs revealed that nidogen-2 directly binds to LGR4 (leucine-rich repeat G-protein-coupled receptor 4) with KD value 26.77 nM. LGR4 deficiency in VSMCs in vitro or in vivo abolished the protective effect of nidogen-2 on vascular calcification. Of interest, nidogen-2 biased activated LGR4-Gαq-PKCα (protein kinase Cα)-AMPKα1 (AMP-activated protein kinase α1) signaling to counteract VSMCs osteogenic transition and mineralization. CONCLUSIONS: Nidogen-2 is a novel endogenous ligand of LGR4 that biased activated Gαq- PKCα-AMPKα1 signaling and inhibited vascular calcification.

BMSCs improve TNBS-induced colitis in rats by inducing Treg differentiation by expressing PD-L1.

OBJECTIVES: Bone marrow-derived mesenchymal stem cells (BMSCs) show promise in treating inflammatory bowel disease. We tested if BMSCs improve Trinitro-benzene-sulfonic acid (TNBS)-induced colitis by inducing Treg differentiation by modulating programmed cell death 1 ligand 1(PD-L1). RESULTS: BMSCs were isolated and transfected with PD-L1 siRNA. Sprague-Dawley rats were randomly divided into 4 groups: normal, model, BMSC control, and PD-L1 siRNA BMSC. Colitis was induced by TNBS, except in the normal group. On d4, the BMSC control and PD-L1 siRNA BMSC groups were intravenously injected with BMSCs at a dose of 5 × 106 cells in phosphate-buffered saline (PBS; volume matched). BMSCs were later verified to have reached the colon tissue. BMSC control showed significantly better clinical symptoms and reduced histopathological colitis severity; PD-L1 siRNA BMSC group showed no difference. PD-L1 siRNA reduced: spleen and mesenteric lymph node Tregs, PD-L1, interleukin-10 (IL10), phosphate and tension homology deleted on chromosome ten (PTEN); colon p-Akt and p-mTOR were increased. CONCLUSIONS: We found that BMSCs can induce Treg differentiation by inhibiting the Akt/mTOR pathway via PD-L1; this significantly improved symptoms and pathology in our ulcerative colitis rat models.

High-Dose Intravenous Iron with Either Ferric Carboxymaltose or Ferric Derisomaltose: A Benefit-Risk Assessment.

The intravenous iron formulations ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) offer the possibility of administering a large amount of iron in one infusion. This results in faster correction of anemia and the formulations being better tolerated than oral iron formulations. This triad of logistic advantages, improved patient convenience, and fast correction of anemia explains the fact that intravenous iron formulations nowadays are frequently prescribed worldwide in the treatment of iron deficiency anemia. However, these formulations may result in hypophosphatemia by inducing a strong increase in active fibroblast growth factor-23 (FGF-23), a hormone that stimulates renal phosphate excretion. This effect is much more pronounced with FCM than with FDI, and therefore the risk of developing hypophosphatemia is remarkably higher with FCM than with FDI. Repeated use of FCM may result in severe osteomalacia, which is characterized by bone pain, Looser zones (pseudofractures), and low-trauma fractures. Intravenous iron preparations are also associated with other adverse effects, of which hypersensitivity reactions are the most important and are usually the result of a non-allergic complement activation on nanoparticles of free labile iron-Complement Activation-Related Pseudo-Allergy (CARPA). The risk on these hypersensitivity reactions can be reduced by choosing a slow infusion rate. Severe hypersensitivity reactions were reported in < 1% of prospective trials and the incidence seems comparable between the two formulations. A practical guideline has been developed based on baseline serum phosphate concentrations and predisposing risk factors, derived from published cases and risk factor analyses from trials, in order to establish the safe use of these formulations.

[Hypophosphatemia: cause or consequence?] / 5 minutes pour apprendre - Hypophosphatémie: cause ou conséquence?

Hypophosphatemia has many causes and is defined as a serum phosphate level lower than 0,80 mmol/l. Severe hypophosphatemia (below 0,32 mmol/l) is due to acute cellular shift and concomitant chronic loss. Glucosuria, defined as more than 1,4 mmol/l of glucose in a random urine sample, is less frequently observed, and has only a few causes. We describe a 52-year-old patient with a possible Fanconi syndrome and resulting seizure due to severe hypophosphatemia (0,26 mmol/l), to emphasize the importance of proper diagnostic work-up for hypophosphatemia in seizure, as it can be the consequence (intracellular shift) or the cause of seizure.

GALNT3 protects against phosphate-induced calcification in vascular smooth muscle cells by enhancing active FGF23 and inhibiting the wnt/ß-catenin signaling pathway.

Vascular calcification (VC) acts as a notable risk factor in the cardiovascular system. Disorder of phosphorus (Pi) metabolism promotes VC. Recent findings show that polypeptide N-acetylgalactosaminyltransferase 3(GALNT3) is Pi responsive and with potent effects on Pi homeostasis. However, whether GALNT3 is involved in high Pi-induced VC remains unclear. The present study investigated the potential role of GALNT3 as a novel regulator of VC. In vitro, human aortic smooth muscle cells (HASMCs) calcification was induced by inorganic Pi, while in vivo, C57BL/6 J mice were used to determine the effects of GALNT3 on Vitamin D3-induced medial arterial calcification. Alizarin red staining, Von Kossa staining, calcium and alkaline phosphatase (ALP) activity were performed to test VC. We showed that expression of GALNT3 was increased in the calcified HASMCs and aortas of the calcified mice.In vitro, overexpression of GALNT3 increased the levels of active full-length FGF23, accompanied by suppression of the osteoblast-related factors (Runx2 and BMP2), and further inhibited the formation of calcified nodules. Moreover, the protein levels of Wnt3a and active ß-catenin were determined and it was found that GALNT3 significantly inhibited their expression. LiCl, a Wnt/ß-catenin signaling activator, was observed to reverse the protective effect of GALNT3 overexpression. The opposite results were observed in the GALNT3 knockdown cells. In vivo, overexpression of GALNT3 by adeno-associated virus decreased the serum Pi and slowed the formation of aortic calcification in the calcified mice. In conclusion, our results indicate that GALNT3 counteracts high Pi-induced osteoblastic differentiation of VSMCs and protects against the initiation and progression of VC by inhibiting the Wnt/ß-catenin signaling pathway.

MiR-708-5p/Pit-1 axis mediates high phosphate-induced calcification in vascular smooth muscle cells via Wnt8b/ß-catenin pathway.

Recently, the underlying mechanism of vascular calcification (VC) has been partially elucidated. However, it is still high incidence, and no effective treatment has been found. This study aims at figuring out the underlying mechanisms of microRNA-708-5p (miR-708-5p)/sodium-phosphate transporter 1 (Pit-1) axis in high phosphate (HP)-induced VC of T/G HA-VSMCs. Alizarin Red S staining was used to evaluate calcium salt deposition, and the activity of alkaline phosphatase (ALP) was determined by measuring the absorbance at 405 nm. RT-qPCR and Western blot were performed to assess the levels of miR-708-5p and Pit-1, the levels of ALP, Pit-1, ß-catenin, glycogen synthesis kinase 3 ß (GSK3ß), and p-GSK3ß proteins, respectively. The interaction between miR-708-5p and Pit-1 was validated by luciferase reporter assay. Our findings illustrated that miR-708-5p was downregulated and Pit-1was upregulated in HP-induced VC. MiR-708-5p mimics inhibited HP-induced VC. Further experiments demonstrated that miR-708-5p targets Pit-1. In addition, miR-708-5p inactivates the Wnt8b/ß-catenin pathway via targeting Pit-1 to reduce HP-induced VC. MiR-708-5p has a crucial effect on VC via targeting Pit-1 and inhibiting Wnt8b/ß-catenin pathway, it may serve as a new target for VC treatment.

A low albumin level as a risk factor for transient severe motion artifact induced by gadoxetate disodium administration: A retrospective observational study with free-breathing dynamic MRI and an experimental study in rats.

OBJECTIVES: In the arterial phase of gadoxetate disodium administration for dynamic MRI, transient severe motion (TSM) sometimes occurs, making image evaluation difficult. This study was to identify risk factors for TSM in a clinical study, and confirm them and investigate the cause in an animal study. METHODS: A retrospective, single-center, observational study included patients who underwent dynamic MRI using gadoxetate disodium for the first time from April 2016 to September 2019 and free-breathing MRI was performed. Differences in clinical characteristics and laboratory tests between the presence and absence of TSM were examined. Animal experiments were conducted in 50 rats; gadoxetate disodium was injected into three sites (distal inferior vena cava (IVC), ascending aorta, and descending aorta) to identify the organ which triggers respiratory irregularities. Phosphate-buffered saline and gadopentetate dimeglumine were also injected into the distal IVC. In addition, to evaluate the effect of albumin, gadoxetate disodium was diluted with phosphate-buffered saline or 5% human serum albumin and injected into the ascending aorta. The time course of the respiratory rate was monitored and evaluated. RESULTS: 20 of 51 (39.2%) patients showed TSM. On multivariable analysis, a low albumin level was an independent risk factor (P = .035). Gadoxetate disodium administration caused significant tachypnea compared to gadopentetate dimeglumine or PBS (an elevation of 16.6 vs 3.0 or 4.3 breaths/min; both P < .001) in rats. The starting time of tachypnea was earlier with injection into the ascending aorta than into the descending aorta (10.3 vs 17.9 sec; P < .001) and the distal IVC (vs 15.6 sec; P < .001). With dilution with albumin instead of phosphate-buffered saline, tachypnea was delayed and suppressed (9.9 vs 13.0 sec; P < .001, 24.1 vs 17.0 breaths/min; P = .031). CONCLUSIONS: A low albumin level is a risk factor for TSM, which could be caused by the effect of gadoxetate disodium on the head and neck region.

Common Dietary Sources of Natural and Artificial Phosphate in Food.

The Recommended Dietary Allowance (RDA) for phosphate in the U.S. is around 700 mg/day for adults. The majority of healthy adults consume almost double the amount of phosphate than the RDA. Lack of awareness, and easy access to phosphate-rich, inexpensive processed food may lead to dietary phosphate overload with adverse health effects, including cardiovascular diseases, kidney diseases and tumor formation. Nutritional education and better guidelines for reporting phosphate content on ingredient labels are necessary, so that consumers are able to make more informed choices about their diets and minimize phosphate consumption. Without regulatory measures, dietary phosphate toxicity is rapidly becoming a global health concern, and likely to put enormous physical and financial burden to the society.

The efficacy and safety of different doses of calcitriol combined with neutral phosphate in X-linked hypophosphatemia: a prospective study.

The present study was the first prospective cohort evaluated the efficacy and safety of different doses of calcitriol in XLH children. The results suggested that a dose of 40 ng/kg/day calcitriol, compared with 20 ng/kg/day, was more effective in relieving the rickets, with similar safety outcomes. Further investigations were expected to set more dose groups. INTRODUCTION: Dose recommended for calcitriol in X-linked hypophosphatemia (XLH) varies in different studies. Therefore, we aimed to compare the efficacy as well as the safety of 20 ng/kg/d and 40 ng/kg/d calcitriol in Chinese XLH pediatrics population. METHODS: A 2-year, randomized, open-label, prospective study recruited 68 XLH children, which were randomized to receive either 40 ng/kg/day or 20 ng/kg/day calcitriol. Efficacy endpoints were the total Thacher ricket severity score (RSS) change from baseline to month 12 and 24, the difference in serum TALP level, fasting serum phosphate level, body height Z-score, and frequency of dental abscess. Safety assessments were done using renal ultrasound nephrocalcinosis grades (0-4), fasting serum and 24 h urine calcium level, and the occurrence of hyperparathyroidism. RESULTS: The decrease in the total RSS from baseline was more significant in the high-dose group at 12 (difference 0.87, p = 0.049) and 24 month (difference 1.23, p = 0.011). The serum TALP level was significantly lower in the high-dose group at 6 months. Pi level, height Z-score change, frequency of dental abscess and ratio of de novo nephrocalcinosis were comparable. A lower incidence of secondary hyperparathyroidism was seen in the high-dose group (p < 0.0001). CONCLUSION: For the first time in this prospective cohort, 40 ng/kg/d calcitriol was shown to be the more effective therapy in XLH children than the 20 ng/kg/d. Moreover, 40 ng/kg/d calcitriol was not associated with increasing adverse events. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT 03,820,518.

Autoantibody of interleukin-17A induced by recombinant Mycobacterium smegmatis attenuates airway inflammation in mice with neutrophilic asthma.

OBJECTIVE: Previous studies have shown Interleukin (IL)-17A as an important contributor to the development of severe asthma, which is mainly characterized by neutrophilic inflammation and less response to corticosteroids. Consequently, the IL-17A-neutrophil axis could be a potential therapeutic target. Previously, we constructed a recombinant Mycobacterium smegmatis (rMS) expressing fusion protein Ag85A-IL-17A, and confirmed it could induce production of IL-17A autoantibody in vivo. This study uses a murine model of neutrophilic asthma to further investigate the effects of rMS on airway inflammation. METHODS: DO11.10 mice were divided into four groups: phosphate buffered saline (PBS), asthma, rMS and MS. This murine model of neutrophilic asthma was established with ovalbumin (OVA) challenge, whereby PBS, rMS and MS were administered intranasally. Anti-inflammatory effects on inflammatory cell infiltration and expression of inflammatory mediators in bronchoalveolar lavage fluid (BALF) were evaluated, along with histopathological changes in lung tissues. RESULTS: A sustained high-titer IL-17A autoantibody was detected in sera of the rMS group. Compared to the asthma group, the number of neutrophils, IL-17A, CXCL-1 levels and MPO activity in the rMS group were all significantly reduced (p < 0.01). Histological analysis showed rMS remarkably suppressed inflammatory infiltration around bronchia. The inflammation score and the mucus score in the rMS group were both significantly lower than those in the asthma group (p < 0.001). CONCLUSION: rMS ameliorated airway inflammation in mice with neutrophilic asthma caused by inducing IL-17A autoantibody and regulating the IL-17A-neutrophil axis, thus offering a possible novel treatment for neutrophilic asthma.

Acute Effects of an Inorganic Phosphorus Additive on Mineral Metabolism and Cardiometabolic Risk Factors in Healthy Subjects.

CONTEXT: Hyperphosphatemia and high levels of fibroblast growth factor 23 (FGF23) are risk factors for cardiovascular events in patients with chronic kidney diseases. However, the impact of an inorganic phosphorus additive in healthy people is largely unknown. OBJECTIVE: We aimed to investigate the acute effect of excessive dietary phosphorus administered as sodium dihydrogen phosphate on the postprandial levels of Pi and FGF23 and the response to food. METHODS: This study was a double-blind placebo-controlled crossover study with 29 healthy male and female participants from the general community who were administered a single dose of either 700 mg phosphorus (NaH2PO4) or a sodium-adjusted placebo in combination with a test meal. Postprandial plasma levels of Pi and FGF23 were measured. RESULTS: Compared with placebo, oral phosphorus increased the plasma Pi level, which remained elevated during the ensuing 8 hours (at 480 minutes: 1.31 vs 1.16 mmol/l; P < 0.001), increased urinary Pi (iAUC0-480 789 vs 95 mmol/mmol; P < 0.001), reduced tubular Pi reabsorption (iAUC0-480 -31.5 vs -6.2; P < 0.001), decreased urinary calcium (iAUC0-240 30.6 vs 53.0 mmol/mmol; P = 0.009), and stimulated the release of parathyroid hormone (iAUC0-480 2212 vs 768 ng/l; P < 0.001). However, the FGF23 levels did not change. Postprandial levels of glucose, insulin, and lipids were not substantially affected by phosphorus vs placebo. CONCLUSION: An oral phosphorus load can induce elevated postprandial levels of circulating Pi for hours in healthy subjects, despite rapid homeostatic counterreactions. FGF23 levels and the postprandial response to food were not affected.