Intestinal Phosphate Absorption Research Articles

7984 A Challenging Case Of Hyperphosphatemic Familial Tumoral Calcinosis

Abstract Disclosure: T.G. de Souza: None. T.J. Weber: None. Introduction: Hyperphosphatemic Familial Tumoral Calcinosis (hFTC) is a rare, autosomal recessive metabolic disorder characterized by elevated serum phosphate levels and the accumulation of calcium phosphate deposits in soft tissues. There are fewer that 150 genetically confirmed cases in the literature. There are no consensus guidelines; therapeutic approaches are guided by case reports or series. This case serves to heighten awareness of therapeutic strategies including global health considerations for the disabled adult with a rare bone disorder. Case: A 32-year-old African-American woman presented to establish care for hFTC, for which she takes ibuprofen for disabling bilateral hip pain. hFTC was diagnosed in early childhood and managed at a large children’s hospital. Therapeutic modalities relied on operative resection of skin lesions on eruption. She describes cosanguinous parentage, consignment to foster care as a child and homelessness as an adult. She has not had adult endocrine care for her hFTC. Her medical comorbidities include major depressive disorder, PTSD and suicide attempt. She reports one uncle with hFTC noting that his phenotype was not significantly disabling and apparent recession of his lesions with age. Her parents did not have symptoms of hFTC. Radiographically, she had amorphous calcium deposits over both hips (her primary sites of severe pain), upper back (site of painless spontaneous eruptions), and left elbow without pain or skin penetration, as well as hyperostosis of the ilium bilaterally. She noticed waxing and waning of her eruptions with her menstrual cycle, such that lesions worsen in the luteal phase. Megestrol acetate also induced new eruptions. Examination shows brown staining to all teeth with several missing teeth. She had a marked lower extremity limb length discrepancy with severe restriction of hip abduction. Blood chemistries were grossly normal, including renal function, calcium, uric acid and PTH. Serum phosphorous was elevated at 5.2 (2.3 - 4.5 mg/dL). CT showed bilateral nephrocalcinosis. We instituted treatment with a low phosphorous diet, sevelamer to reduce intestinal phosphate absorption and acetazolamide to increase urinary phosphate excretion. For her pain and functional disability, we recommended continued NSAIDs, physical therapy and social work consultation to facilitate continued access to care. Conclusions: This case uniquely describes hFTC symptom fluctuation with the menstrual cycle, worsening with increased progesterone, suggesting a possible role of gonadal hormones on FGF-23 biology. It also highlights the socioeconomic burdens that can accompany rare bone disease, which become more pronounced as the patient achieves adulthood. Successful transition of care from pediatric to adult endocrinologist, in addition to engaging multi-disciplinary support, is essential in optimizing life-long care in hFTC. Presentation: 6/1/2024

Muscle weakness after intravenous iron replacement

After a young female patient received an intravenous iron infusion for severe symptomatic iron-deficiency-anemia, a severe hypophosphatemia was diagnosed with associated mild muscle weakness. With renal phosphate loss and elevated serum FGF23 (Fibroblast Growth Factor 23), the diagnosis of a hypophosphatemia caused by ferric carboxymaltose was made. Upregulation of FGF23 inhibits renal phosphate reabsorption and also the activation of vitamin D, which additionally reduces intestinal phosphate absorption. The symptoms of hypophosphatemia may be masked after iron replacement.

Absence of claudin-3 does not alter intestinal absorption of phosphate in mice

Intestinal absorption of phosphate is bimodal, consisting of a transcellular pathway and a poorly characterized paracellular mode, even though the latter one contributes to the bulk of absorption under normal dietary conditions. Claudin-3 (Cldn3), a tight junction protein present along the whole intestine in mice, has been proposed to tighten the paracellular pathway for phosphate. The aim of this work was to characterize the phosphate-related phenotype of Cldn3-deficient mice. Cldn3-deficient mice and wildtype littermates were fed standard diet or challenged for 3 days with high dietary phosphate. Feces, urine, blood, intestinal segments and kidneys were collected. Measurements included fecal, urinary, and plasma concentrations of phosphate and calcium, plasma levels of phosphate-regulating hormones, evaluation of trans- and paracellular phosphate transport across jejunum and ileum, and analysis of intestinal phosphate and calcium permeabilities. Fecal and urinary excretion of phosphate as well as its plasma concentration was similar in both genotypes, under standard and high-phosphate diet. However, Cldn3-deficient mice challenged with high dietary phosphate had a reduced urinary calcium excretion and increased plasma levels of calcitriol. Intact FGF23 concentration was also similar in both groups, regardless of the dietary conditions. We found no differences either in intestinal phosphate transport (trans- or paracellular) and phosphate and calcium permeabilities between genotypes. The intestinal expression of claudin-7 remained unaltered in Cldn3-deficient mice. Our data do not provide evidence for a decisive role of Cldn3 for intestinal phosphate absorption and phosphate homeostasis. In addition, our data suggest a novel role of Cldn3 in regulating calcitriol levels.

The Relevance of Phytate for the Treatment of Chronic Kidney Disease.

Diets high in plant-based foods are commonly recommended for people with chronic kidney disease (CKD). One putative advantage of these diets is reduced intestinal phosphate absorption. This effect has been ascribed to phytic acid (myoinositol hexaphosphoric acid) and its anion, phytate, that are present in many plant foods, particularly in the seeds, nuts, grains and fruits of plants. This paper reviews the structure and many actions of phytate with particular reference to its potential effects on people with CKD. Phytate binds avidly to and can reduce gastrointestinal absorption of the phosphate anion and many macrominerals and trace elements including iron, zinc, calcium and magnesium. This has led some opinion leaders to label phytate as an "anti-nutrient." The human intestine lacks phytase; hence, phytate is essentially not degraded in the small intestine. A small amount of phytate is absorbed from the small intestine, although phytate bound to phosphate is poorly absorbed. Clinical trials in maintenance hemodialysis patients indicate that intravenously administered phytate may decrease hydroxyapatite formation, vascular calcification and calciphylaxis. Orally administered phytate or in vitro studies indicate that phytate may also reduce osteoporosis, urinary calcium calculi formation and dental plaque formation. Phytate appears to have anti-inflammatory and antioxidant effects, at least partly due to its ability to chelate iron. Other potential therapeutic roles for phytate, not definitively established, include suppression of cancer formation, reduction in cognitive decline that occurs with aging, and amelioration of certain neurodegenerative diseases and several gastrointestinal and metabolic disorders. These latter potential benefits of phytate are supported by cell or animal research or observational studies in humans. Many of the above disorders are particularly common in CKD patients. Definitive clinical trials to identify potential therapeutic benefits of phytate in CKD patients are clearly warranted.

Safety and efficacy of burosumab in improving phosphate metabolism, bone health, and quality of life in adolescents with X-linked hypophosphatemic rickets

Background and objectiveX-linked hypophosphatemic rickets (XLH) is due to loss-of-function mutations in the phosphate-regulating endopeptidase homologue on the X chromosome (PHEX) that lead to increased fibroblast growth factor 23 (FGF23) production. FGF23 excess causes renal phosphate wasting and insufficient 1,25-dihydroxyvitamin D (1,25(OH)2D) synthesis with reduced intestinal phosphate absorption, ultimately resulting in chronic hypophosphatemia.Children with XLH show typical skeletal lesions of rickets, deformities of the lower limbs, stunted growth with disproportionate short stature, bone pain, and physical dysfunctions.Burosumab, a fully human IgG1 monoclonal antibody that binds to FGF23 to inhibit its activity, is more effective to improve the biochemical and clinical signs of XLH than conventional treatment with phosphate supplements and vitamin D active metabolites. Data on adolescents with XLH during the transition period to young adulthood are few.In this prospective case series, we aimed to assess safety and efficacy of burosumab in adolescents with XLH who discontinued long-term conventional therapy. MethodsFive Caucasian adolescents (4 males, 1 female; mean age 15.4 ± 1.5 years) with XLH were recruited and switched from conventional treatment to burosumab (0.8–1.2 mg/kg, s. c. QW2). Burosumab was continued for 12–48 months and, once discontinued, patients were followed-up for 6–12 months. In all patients, serum calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and 1,25(OH)2D levels, and renal tubular reabsorption of phosphate (TmP/GFR) values were assessed at entry and during burosumab. Intact FGF23 plasma levels were measured at entry. Patient-reported outcomes (PROs) were assessed at entry and every 3–6 months to evaluate the impact of low extremity pain, stiffness, and difficulties performing daily activities. ResultsAt entry, all patients showed hypophosphatemia, increased intact FGF23 levels, reduced TmP/GFR, insufficient 1,25(OH)2D levels, and in four out of five increased ALP levels. Two patients had radiological signs of rickets. During burosumab, all patients showed a significant increase in serum phosphate and 1,25(OH)2D levels, and in TmP/GFR values (P < 0.05 - P < 0.0001). Serum ALP levels significantly declined (P < 0.05) to normal values. No changes of serum calcium and PTH levels (PNS) were found during burosumab. PROs significantly improved (P < 0.02 - P < 0.0001) in all patients. Four patients discontinued burosumab when they turned 18 or 19, whereas one continued the treatment since he was still younger than 18 during the study period. Four patients who suspended burosumab showed a rapid decline in serum phosphate and 1,25(OH)2D levels and in TmP/GFR values; serum ALP levels increased, and PROs progressively worsened with a significant reduction in quality of life. These consequences were not observed in the patient who continued burosumab treatment. DiscussionOur data showed that conventional treatment improved only in part the signs and symptoms of XLH. Burosumab was well tolerated and was effective in improving phosphate metabolism, bone health, and PROs. All the benefits of burosumab were lost after its discontinuation. These results suggested that continuing burosumab is required to achieve and maintain the clinical benefits of the treatment during the transition to young adulthood in patients with XLH.

Effect of an NHE3 inhibitor in combination with an NPT2b inhibitor on gastrointestinal phosphate absorption in Rodent models.

Many of the pathological consequences of chronic kidney disease can be attributed to an elevation in serum phosphate levels. Current therapies focused on decreasing intestinal phosphate absorption to treat hyperphosphatemia are inadequate. The most effective therapeutic strategy may be to target multiple absorptive pathways. In this study, the ability of a novel inhibitor of the intestinal sodium hydrogen exchanger 3 (NHE3), LY3304000, which inhibits paracellular, diffusional uptake of phosphate, to work in combination with an inhibitor of the active transporter, sodium dependent phosphate cotransporter 2b (NPT2b), LY3358966, was explored. LY3304000 modestly inhibited the acute uptake of phosphate into plasma of rats, while surprisingly, it doubled the rate of phosphate uptake in mice, an animal model dominated by NPT2b mediated acute phosphate uptake. In rats, LY3004000 and LY3358966 work in concert to inhibit acute phosphate uptake. On top of LY3358966, LY3304000 further decreased the acute uptake of phosphate into plasma. Studies measuring the recovery of radiolabeled phosphate in the intestine demonstrated LY3304000 and LY3358966 synergistically inhibited the absorption of phosphate in rats. We hypothesize the synergism is because the NHE3 inhibitor, LY3304000, has two opposing effects on intestinal phosphate absorption in rats, first it decreases diffusion mediated paracellular phosphate absorption, while second, it simultaneously increases phosphate absorption through the NPT2b pathway. NHE3 inhibition decreases proton export from enterocytes and raises the cell surface pH. In vitro, NPT2b mediated phosphate transport is increased at higher pHs. The increased NPT2b mediated transport induced by NHE3 inhibition is masked in rats which have relatively low levels of NPT2b mediated phosphate transport, by the more robust inhibition of diffusion mediated phosphate absorption. Thus, the inhibition of NPT2b mediated phosphate transport in rats in the presence of NHE3 inhibition has an effect that exceeds its effect in the absence of NHE3 inhibition, leading to the observed synergism on phosphate absorption between NPT2b and NHE3 inhibition.

Significance of phosphate in internal medicine

Phosphate is essential for bone metabolism and for energy provision. Phosphate homeostasis is achieved by hormonal feedback mechanisms, predominantly parathyroid hormone, fibroblast growth factor 23 and calcitriol, with renal phosphate absorption taking on a special role. Although even large deviations from the serum normal range are rarely symptomatic, the health consequences can be significant. Essentially, the clinically relevant disturbances in phosphate balance can be attributed to three mechanisms: 1. shifts of phosphate between the extracellular space and the cytosol; 2. inadequate phosphate reabsorption in the kidney; 3. decreased intestinal phosphate absorption. Knowledge of physiology enables diagnosis and therapy of phosphate disorders.

Tenapanor-A Novel Approach for Management of Hyperphosphatemia in End Stage Renal Disease: A Clinical Study Aggregate Review

The critical importance of phosphate regulation in chronic kidney disease (CKD) has been well understood for decades. But new findings, frequently applicable to routine medical care, continue to evolve. Poor health outcomes, greater morbidity, lowered quality of life, and a higher death rate from cardiovascular disease are all linked to the development of CKD-bone mineral ailment. Increased blood phosphate levels are linked to an increased risk of mortality in hemodialysis patients due to changes in phosphate breakdown and declining renal function as CKD advances.In this setting, according to CKD-mineral bone disease recommendations, it is critical to regulate serum phosphate levels in patients with CKD-mineral bone problem. If dialysis and dietary intervention fail to control blood phosphate levels, the use of phosphate binders is advised. Although phosphate binders are successful in lowering blood phosphate levels by actively binding to dietary phosphate, certain individuals have adverse effects that may restrict their use.These medications also have a significant pill load, which might result in poor treatment compliance. Tenapanor, a novel medication, works by inhibiting the sodium/hydrogen exporter isoform 3 (NHE3), which lowers intestinal phosphate absorption primarily by decreasing passive paracellular phosphate flow. Tenapanor also reduces the expression of the sodium phosphorus 2b transport protein (NaPi2b), which limits active transcellular phosphate absorption compensation. This is considered to be more effective phosphorous absorption regulator and a better target for tailored medication therapy. This clinical study aggregate report explores the currently published studies that have evaluated Tenapanor for the treatment of hyperphosphatemia in end stage renal disease patients on haemodialysis.&#x0D; Keywords: Tenapanor, phosphate binding agents, hyperphosphatemia, chronic kidney disease, phosphate control, phosphate binders, phosphate absorption, phosphate absorbtion inhibitor.

Effects of the novel sodium-dependent phosphate cotransporter 2b inhibitor DZ1462 on hyperphosphatemia in chronic kidney disease.

Serum phosphate levels remain insufficiently controlled in chronic kidney disease (CKD) patients, and novel therapeutic strategies are needed. Blocking intestinal phosphate absorption mediated by sodium-dependent phosphate cotransporter type 2b (NPT2b) holds promise as one such strategy. The in vitro cellular potency of DZ1462 was evaluated using a radioactive Pi uptake assay on stable Chinese hamster ovary (CHO) cell clones transfected with human NPT2b (hNPT2b) or rat NPT2b (rNPT2b). The ability of DZ1462 to inhibit phosphate absorption was studied in vivo in an acute model after oral bolus challenge with 33PO4 and in an adenine-induced chronic hyperphosphatemia rat model. PK and minitox was also evaluated. The cellular assays with the hNPT2b-CHO and rNPT2b-CHO clones showed that DZ1462 significantly and potently inhibited phosphate uptake. In vivo, in a chronic Pi-fed rat model, DZ1462 effectively inhibited intestinal Pi uptake. In a hyperphosphatemia rat model, DZ1462 significantly inhibited Pi uptake, and DZ1462 in combination with sevelamer had a synergistic effect. The pharmacokinetics (PK) study confirmed that DZ1462 is a gastrointestinal (GI)-restricted compound that can remain in the intestine for a sufficient duration. In addition, DZ1462 also reduced cardiovascular events and ameliorated osteoporosis in a CKD animal model. This study revealed that a GI-restricted NPT2b inhibitor DZ1462 potently inhibits NPT2b in vitro and blocks intestinal phosphate uptake in multiple animal models with potential to reduce various cardiovascular events in CKD models. Therefore, DZ1462 may be useful to treat renal disease patients who have shown an unsatisfactory response to phosphate binders.

Long-term safety and decrease of pill burden by tenapanor therapy: a phase 3 open-label study in hemodialysis patients with hyperphosphatemia

Phosphate binders (PBs) generally have a high pill burden. Tenapanor selectively inhibits sodium/hydrogen exchanger isoform 3, reducing intestinal phosphate absorption. Tenapanor is a novel drug administered as a small tablet, twice daily. This multicenter, open-label, single-arm, phase 3 study aimed to evaluate the long-term safety of tenapanor and its efficacy in decreasing PB pill burden. Tenapanor 5 mg twice daily was administered to hemodialysis patients with serum phosphorus level 3.5–7.0 mg/dl at baseline; the dose could be increased up to 30 mg twice daily. Patients could also switch from PBs. The primary endpoint was safety during 52-week administration. The key secondary endpoint was a ≥ 30% reduction in the total pill number of daily PBs and tenapanor from baseline. Of 212 patients starting treatment, 154 completed the study. Diarrhea was the most frequent adverse event, occurring in 135 patients (63.7%); most events were classified as mild (74.8%). No clinically significant changes occurred other than serum phosphorus level. At Week 52/discontinuation, 158/204 patients (77.5%) achieved the key secondary endpoint. Complete switching from PBs to tenapanor was achieved in 50–76 patients (26.7%–41.5%), and 80 patients (51.9%) at Week 8–12 and Week 50, respectively. Serum phosphorus remained generally stable within the target range (3.5–6.0 mg/dl). These findings suggest the long-term safety and tolerability of tenapanor. Tenapanor could reduce or eliminate PB pill burden while controlling serum phosphorus levels.Trial registration: NCT04771780

Constipation in Patients With Chronic Kidney Disease.

Constipation is a frequent symptom in patients with chronic kidney disease (CKD). This review outlines the mechanisms and management of constipation in patients with CKD from a physician's perspective. Common causes of constipation in patients with CKD include concomitant medications, low dietary fiber intake, water-restricted diet, lack of physical activity, altered gut microbiota, and reduced gastrointestinal motility. Constipation has a negative impact on overall health, and, in particular, the presence of constipation has been associated with worsening kidney function and increased risk of developing advanced stages of CKD. Although lifestyle and dietary modifications may not always be practical for patients with CKD, they are recommended because they are beneficial as they lower mortality in patients with CKD. The use of laxatives containing magnesium salts, bulking agents, and osmotic laxatives may have insufficient efficacy and may be associated with adverse effects. In contrast, lactulose and lubiprostone have been shown to exhibit reno-protective effects. Linaclotide and plecanatide have very limited systemic absorption and appear safe in patients with CKD. Tenapanor reduces paracellular intestinal phosphate absorption in addition to blocking sodium uptake by enterocytes, and provides additional benefit in patients patients with CKD who have hyperphosphatemia and constipation. Prucalopride leads to improvements in bowel function and constipation-related symptoms in cases in which response to conventional laxatives are inadequate. However, the dose of prucalopride should be reduced to 1 mg once daily for patients with CKD. In conclusion, there are important advances on the impact and treatment of constipation in patients with CKD.

Increased Slc34a2 expression and paracellular phosphate permeability contribute to high intestinal phosphate absorption in young mice.

Phosphorus is a critical constituent of bone as a component of hydroxyapatite. Bone mineral content accrues rapidly early in life necessitating a positive phosphorus balance, which could be established by a combination of increased renal reabsorption and intestinal absorption. Intestinal absorption can occur via a transcellular pathway mediated by the apical sodium-phosphate cotransporter, Slc34a2/NaPiIIb or via the paracellular pathway. We sought to determine how young mammals increase dietary phosphorus absorption from the small intestine to establish a positive phosphorus balance, a prerequisite for rapid bone growth. The developmental expression profile of genes mediating phosphate absorption from the small intestine was determined in mice by qPCR and immunohistochemistry. Additionally, Ussing chamber studies were performed on small bowel of young (p7-p14) and older (8- to 17-week-old) mice to examine developmental changes in paracellular Pi permeability and transcellular Pi transport. Blood and urinary Pi levels were higher in young mice. Intestinal paracellular phosphate permeability of young mice was significantly increased relative to older mice across all intestinal segments. NaPiIIb expression was markedly increased in juvenile mice, in comparison to adult animals. Consistent with this, young mice had increased transcellular phosphate flux across the jejunum and ileum relative to older animals. Moreover, transcellular phosphate transport was attenuated by the NaPiIIb inhibitor NTX1942 in the jejunum and ileum of young mice. Our results are consistent with young mice increasing phosphate absorption via increasing paracellular permeability and the NaPiIIb-mediated transcellular pathway.

A case report on anti-epileptic drugs associated cerebral palsy and rickets

Seizures are incredibly widespread all around the world, today. A seizure is often described as a transient alteration in the electrical activity of the brain. This required the treatment with antiepileptic drugs (AEDs). The majority of AEDs lower vitamin D levels. Vitamin D is found to be crucial for intestinal absorption of calcium, magnesium, and phosphate which helps to build and mineralize bones. Vitamin D deficiency has been seen to be a causative reason for cerebral palsy which is a neurological illness that affects movement and muscle coordination, permanently. It has been observed to manifest in infancy or early childhood due to vitamin D deficiency due to long term use of AEDs making it severe due to malnourishment. This case reports the use of antiepileptic drugs leading to cerebral palsy due to vitamin D deficiency. Therefore, by this case report we want to alert the readers and healthcare professionals about the possible adverse effects of AEDs and to be aware of them.

Intact FGF23 predicts serum phosphate improvement after combined nicotinamide and phosphate binder treatment in hemodialysis patients.

Hyperphosphatemia is associated with increased mortality and cardiovascular morbidity of end-stage kidney failure (ESKF) patients. Managing serum phosphate in ESKF patients is challenging and mostly based on limiting intestinal phosphate absorption with low phosphate diets and phosphate binders (PB). In a multi-centric, double-blinded, placebo-controlled study cohort of maintenance hemodialysis patients with hyperphosphatemia, we demonstrated the efficacy of nicotinamide modified release (NAMR) formulation treatment in addition to standard PB therapy in decreasing serum phosphate. Here we aimed to assess the relationship between phosphate, FGF23, inflammation and iron metabolism in this cohort. We measured the plasma concentrations of intact fibroblast growth factor 23 (iFGF23) and selected proinflammatory cytokines at baseline and Week 12 after initiating treatment. We observed a strong correlation between iFGF23 and cFGF23 (C-terminal fragment plus iFGF23). We identified iFGF23 as a better predictor of changes in serum phosphate induced by NAMR and PB treatment compared with cFGF23. Recursive partitioning revealed at baseline and Week 12, that iFGF23 and cFGF23 together with T50 propensity were the most important predictors of serum phosphate, whereas intact parathyroid hormone (iPTH) played a minor role in this model. Furthermore, we found serum phosphate and iPTH as the best predictors of iFGF23 and cFGF23. Sex, age, body mass index, and markers of inflammation and iron metabolism had only a minor impact in predicting FGF23. Lowering serum phosphate in ESKF patients may depend highly on iFGF23 which is correlated to cFGF23 levels. Serum phosphate was the most important predictor of plasma FGF23 in this ESKF cohort.

Klf4-Sirt3/Pparα-Lcad pathway contributes to high phosphate-induced lipid degradation

BackgroundPhosphorus commonly reduces lipid deposition in the vertebrates. However, the underlying mechanisms involved in the process remain unclear.MethodsYellow catfish were given three experimental diets with dietary phosphate levels of 3.22, 6.47 and 7.99 g Pi kg− 1, respectively, for 8 weeks. The contents of triglyceride, non-esterified free fatty acids, adenosine triphosphate, nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide, enzymatic activities, mRNA and protein expression were determined in the intestinal tissues. Hematoxylin and eosin, Oil Red O staining, and transmission electron microscope were performed for intestinal tissues. Primary intestinal epithelial cells were isolated from yellow catfish intestine. Western blot analysis, Immunoprecipitation assays, Immunofluorescence staining, and RNA extraction and quantitative real-time PCR were decided. Luciferase reporter assays and electrophoretic mobility shift assay were used to evaluate the function of Sirt3, PPARα and Lcad promoters.ResultsHigh dietary phosphate intake activated intestinal phosphate absorption and excretion, and reduced lipid deposition through increasing lipolysis in the intestine. Moreover, phosphate incubation increased the mRNA and protein expression of krüppel like factor 4 (klf4), silent mating-type information regulation 2 homolog 3 (sirt3), peroxisome proliferator activated receptor alpha (pparα) and long chain acyl-CoA dehydrogenase (lcad) in the intestinal epithelial cells (IECs), and klf4 knockdown attenuated the phosphate-induced increase of protein levels of Sirt3, Pparα and Lcad. Further investigation found that Klf4 overexpression increased the activity of sirt3 and pparα promoters, which in turn reduced the acetylation and protein level of Lcad.ConclusionDietary Pi excess induced lipid degradation by the activation of the Klf4-Sirt3/Pparα-Lcad pathway in the intestine and primary IECs.Graphical 2J2H-vAY8k8xL15UHAsvLYVideo

An overview of fibroblast growth factor 23 and its role in kidney function

Fibroblast growth factor 23 (FGF23) is a hormone that plays a critical role in regulating mineral homeostasis in the body. Specifically, FGF23 acts on the kidneys to decrease the reabsorption of phosphate from the blood and into the urine. This process helps to reduce serum phosphate levels and maintain balance alongside other hormones such as PTH. The primary responsibility of FGF23 is to regulate the balance of phosphate in the body. It does this by acting on the kidney cells to decrease the reabsorption of phosphate from the blood and into the urine. This process allows the body to excrete excess phosphate to maintain normal serum phosphate levels in the blood. In addition to regulating phosphate levels, FGF23 also plays a role in the metabolism of vitamin D. FGF23 can increase the metabolism of vitamin D to an inactive form, reducing the amount of active vitamin D in the body. This reduction in active vitamin D levels leads to decreased intestinal absorption of dietary calcium and phosphate. Abnormal levels of FGF23 in the body have been associated with several health concerns, particularly in patients with chronic kidney disease. High levels of FGF23 have been linked to the development of bone loss, vascular calcification, and cardiovascular disease. Conversely, low levels of FGF23 have been associated with an increased risk of mortality and cardiovascular disease in patients with kidney disease.

Osteomalacia Is Not a Single Disease

Among bone-material qualities, mineralization is pivotal in conferring stiffness and toughness to the bone. Osteomalacia, a disease ensuing from inadequate mineralization of the skeleton, is caused by different processes leading to decreased available mineral (calcium and/or phosphate) or enzymatic alterations. Vitamin D deficiency, which remains the major cause of altered mineralization leading to inadequate intestinal calcium and phosphate absorption, may be also associated with other conditions primarily responsible for abnormal mineralization. Given the reality of widespread vitamin D inadequacy, a full biochemical assessment of mineral metabolism is always necessary to rule out or confirm other conditions. Both too-high or too-low serum alkaline phosphatase (ALP) levels are important for diagnosis. Osteomalacic syndrome is reversible, at least in part, by specific treatment. Osteomalacia and bone mineralization themselves constitute largely unexplored fields of research. The true prevalence of the different forms of osteomalacia and the recovery after proper therapy have yet to be determined in the real world. Although non-invasive techniques to assess bone mineralization are not available in clinical practice, the systematic assessment of bone quality could help in refining the diagnosis and guiding the treatment. This review summarizes what is known of osteomalacia recent therapeutic developments and highlights the future issues of research in this field.

PSAT223 A Delayed Diagnosis of Oncogenic Osteomalacia Presenting with Bone Pain, Muscle Weakness and Elevated Alkaline Phosphatase

Abstract Background Tumor-induced osteomalacia (TIO) is a rare bone disease caused by excess production of FGF23 by a phosphaturic mesenchymal tumor, resulting in severe hypophosphatemia, bone demineralization, insufficiency fractures, bone pain and muscle weakness. The Fibroblast Growth Factor-23 (FGF23) is a phosphaturic hormone produced by osteocytes, whose primary effect is to decrease serum phosphate by suppressing proximal tubular phosphate reabsorption and intestinal phosphate absorption (via diminished 1,25D production). Clinical case A 65-year-old male was referred to endocrinology clinic for a second opinion due to severe rib pain and elevated alkaline phosphatase levels. His first endocrinologist diagnosed Paget's disease of the bone based on symptoms of rib pain, an elevated alkaline phosphatase level, and abnormal Tc99 bone scintigraphy demonstrating uptake in multiple areas, including bilateral humeri, ribs, knees, ankles, and L4 vertebral body. He received 5 mg IV zoledronate for treatment of Paget's disease, and immediately post-infusion reported worsening of severe rib pain. Upon presentation to our institution, he reported ongoing severe rib pain and bilateral knee pain. On exam, he had extreme difficulty rising from a seated position. Laboratories revealed calcium 9.0 mg/dL, albumin 5.0 g/dL, alkaline phosphatase 116 U/L, 25D 43 ng/dL, PTH 66 pg/mL and serum phosphorous 1.5 mg/dL. Tubular Reabsorption of Phosphate (TRP) was 59%, based on a spot second morning void with corresponding fasting morning blood draw. 1,25D was 13 pg/mL (19-79 pg/mL). Intact FGF23 was 346 pg/mL (&amp;lt;59 pg/nL). CT revealed bilateral tibial plateau insufficiency fractures. When asked if he noticed any "lumps or bumps", the patient reported a lump under his left second toe. MRI showed a 1.8 cm soft tissue mass. A GA68-DOTA-TATE PET CT revealed a 2.3 cm soft tissue mass plantar to the 2nd left proximal phalanx with intense activity mass (SUVmax 39.8). This mass was surgically excised. Post-operative FGF23 levels were as follows: 38 pg/mL → 15 pg/mL → &amp;lt;14 pg/mL. Within 14 days, the patient's ability to rise from a seated position was markedly improved. His severe rib pain persisted for three weeks but was significantly improved by six weeks post-op. Despite treatment with 1 mcg calcitriol daily and 5000 IU vitamin D daily, he developed evidence of post-operative hungry bone syndrome with calcium 8.3 mg/dL, PTH 64 pg/mL, and alk phos 157 U/L. Conclusion Tumor-induced osteomalacia is a rare but treatable condition, presenting with severe hypophosphatemia, bone pain, bone demineralization, insufficiency fractures, and muscle weakness. Due to the nonspecific nature of the presenting symptoms, delays in diagnosis are common. Serum phosphorous should be obtained in all patients presenting with unexplained elevations in alkaline phosphatase. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

39-Year-Old Woman With Severe Weakness

39-Year-Old Woman With Severe Weakness

Development of potent non-acylhydrazone inhibitors of intestinal sodium-dependent phosphate transport protein 2b (NaPi2b)

Inhibition of intestinal sodium-dependent phosphate transport protein 2b (NaPi2b), responsible for intestinal phosphate absorption, is considered to reduce serum phosphate levels, making it a promising therapeutic approach for hyperphosphatemia. Previously, we aimed to identify new drugs for hyperphosphatemia treatment and obtained zwitterionic compound 3 (IC50 = 64 nM) as a potent selective inhibitor of intestinal NaPi2b. This small-molecule compound is gut-restricted owing to its almost membrane-impermeable property. However, when compound 3, containing an acylhydrazone structure, is exposed to plasma, it is easily metabolized and likely produces an acetylhydrazine compound. Clinical studies have shown that acetylhydrazine is a risk factor for hepatic toxicity owing to its microsomal metabolism, wherein toxic reactive intermediates are formed.Therefore, in this study, we aimed to obtain potent NaPi2b inhibitors without an acylhydrazone structure to reduce the risk of hepatic toxicity. We developed compound 18, an anilide compound with zwitterionic property having potent phosphate uptake inhibitory activity in vitro (IC50 = 14 nM) and low bioavailability (FaFg = 5.9%). Oral administration of compound 18 in rats showed a reduction in phosphate absorption comparable to that observed with lanthanum carbonate, a clinically effective phosphate binder used in hyperphosphatemia treatment. Moreover, combined administration of compound 18 and lanthanum carbonate resulted in an additive effect on phosphate absorption inhibition in rats. Our findings suggest that combination therapy with lanthanum carbonate and compound 18 will not only provide better treatment outcomes for hyperphosphatemia but also reduce gastrointestinal side effects in patients.