Fibroblast Growth Factor 23 Levels Research Articles

Circular RNA circLRCH3 promotes oxaliplatin resistance in gastric cancer through the modulation of the miR-383-5p/FGF7 axis.

Gastric cancer (GC) is a common malignant tumor of the digestive system. Circular RNAs (circRNAs) play a vital role in tumorigenesis and chemoresistance. The current study aimed to explore the possible role and mechanism of circRNA leucine rich repeats and calponin homology domain containing 3 (circLRCH3) in GC chemoresistance. The levels of circLRCH3, microRNA-383-5p (miR-383-5p) and fibroblast growth factor 7 (FGF7) were determined by quantitative real-time PCR or Western blot. Cell Counting Kit-8 (CCK-8) assay was utilized to evaluate cell survival rate and proliferation ability. Colony formation, transwell and flow cytometry assays were used to assess cell proliferation, migration, invasion and apoptosis. The expression of multidrug resistance proteins was detected by Western blot. The binding relationship between miR-383-5p and circLRCH3/FGF7 was verified by dual-luciferase reporter assay or RNA immunoprecipitation assay. Xenograft assay was conducted to analyze the role of circLRCH3 in OXA resistance in vivo. CircLRCH3 and FGF7 levels were up-regulated, while miR-383-5p level was reduced in OXA-resistant GC tissues and cells. Depletion of circLRCH3 attenuated the resistance of OXA-resistant cells to OXA. CircLRCH3 silence reduced OXA resistance by regulating miR-383-5p. Besides, miR-383-5p elevated OXA sensitivity of GC cells by repressing FGF7. Moreover, the deletion of circLRCH3 increased OXA sensitivity in vivo. Knockdown of circLRCH3 alleviated OXA resistance of GC by modulating the miR-383-5p/FGF7 axis, which provided a promising therapeutic target for GC chemoresistance.

TUMOR INDUCED OSTEOMALACIA: A CASE REPORT

Background:Tumor-induced osteomalacia (TIO), which is also known as oncogenic osteomalacia, is an uncommon paraneoplastic syndrome characterized by a renal phosphate loss causing hypophosphatemia, leading to rickets in children and osteomalacia in adults. It is caused by mesenchymal tumors, which secrete FGF-23 (fibroblast growth factor-23) and rarely other phosphotonins. It can present with a wide range of symptoms and there is often a delay in its diagnosis. Early diagnosis is important and surgical excision can cure the disease in most patients, thus preventing the complications.We report a case of TIO, who was diagnosed at an early stage and underwent curative surgery. Case presentation: A 30 years old female presented with pain in both legs, more severe in the left leg since about 1 year. She also had difficulty in walking, low back ache, muscle pain, mild pain in both the knee joints as well. On examination, she had limping gait, muscle power in the left leg was grade 3-4 otherwise, there was no significant findings on examination. Blood investigations showed elevated alkaline phosphatase (ALP)- 387IU/ml, low serum phosphorus- 1.2mg/dl, normal calcium - 9.8mg/dl, 25-OH Vitamin D- 24.69ng/ml, Parathyroid hormone (PTH)- 61pg/ml.Other blood tests were unremarkable. X- rays of both the legs and pelvis showed a classicalpseudo-fracture in proximal part of both the fibulae and proximal part of the right femur. This suggested hypophosphatemicosteomalacia. TmP/GFR was found to be very low (1.4mg/dl), which confirmed renal phosphate wasting. Later we got Fibroblast growth factor – 23 (FGF-23)- 617RU/ml, which was elevated. This confirmed FGF-23 related hypophosphatemicosteomalacia. In view of the patients age, onset of symptoms, lack of family history, absence of dental and hearing abnormalities, we suspected an acquired rather than a genetic cause. The patient underwent whole body Gallium-68 DOTANOC PET scan, which revealed somatostatin receptor expressing soft tissue density lesion in subcutaneous plane in the mid- anterior right leg, suggestive of FGF-23 secreting mesenchymal tumor.The patient was initially treated with replacement dose of oral phosphorus and calcitriol, along with calcium and vitamin D supplements. Later the patient underwent surgery for excision of the tumor in the right leg. The tumor was around 2cm size and the histopathology was suggestive of gaint cell rich tumor- possibly a phosphaturic mesenchymal tumor. Post surgery, the patient had significant improvement in her symptoms, gait improved and pain reduced. The serum phosphorus level was 3.8mg/dl post-operatively. The serum phosphorus level was maintained without phosphorus replacement. The patient was advised to repeat FGF-23 levels, but the patient failed to get it done. Conclusion: The diagnosis of TIO requires high index of suspicion and should always be looked as a differential diagnosis when we are evaluating a patient with osteomalacia. A detailed history and examination followed by a step wise biochemical evaluation and imaging is important to diagnose TIO in early stages. Surgical resection of the causative tumor will lead to definitve cure of the disease in most patients and avoids the complications like osteoporosis and fractures, thus improving the quality of life of the patients.

Tumour induced osteomalacia in patients with malignancy: a meta-analysis and systematic review of case reports.

Tumour induced osteomalacia (TIO) due to FGF23 overexpression is becoming recognized in patients with malignancy. The condition may be underdiagnosed, with a scarce medical literature. To perform a meta-analysis of case reports to allow a better understanding of malignant TIO and its clinical implications. Full-texts were selected according to strict inclusion criteria. All case reports were included where patients had hypophosphatemia, malignant TIO, and FGF23 blood levels. 32/275 eligible studies (n = 34 patients) met inclusion criteria. A list of desired data was extracted and graded for methodological quality. Prostate adenocarcinoma (n = 9) were the most tumours reported. 25/34 patients had a metastatic disease and a poor clinical outcome was reported for 15/28 patients. The median levels of blood phosphate and C-terminal FGF23 (cFGF23) were 0.40 mmol/L and 788.5 RU/mL respectively. For most of patients, blood PTH was elevated or within range, and calcitriol levels were inappropriately low or normal. Alkaline phosphatase concentrations were increased for 20/22 patients. The cFGF23 values were significantly higher for patients with a poor clinical outcome when compared to other patients (1685 vs 357.5 RU/mL). In case of prostate cancer, cFGF23 levels were significantly lower (429.4 RU/mL) than for other malignancies (1007.5 RU/mL). We report for the first time a detailed description of the clinical and biological characteristics of malignant TIO. In this context, FGF23 blood measurement would be of value for the diagnostic work-up, prognostication and follow-up of patients.

Controlled Attenuation Parameter Is Associated with a Distinct Systemic Inflammatory Milieu after Clearance of HCV Infection

Hepatitis C virus (HCV) infection is closely associated with lipid metabolism defects along with a high prevalence of hepatic steatosis. After HCV clearance, steatosis persists in many patients. However, the reasons behind this phenomenon are not completely clear. To investigate the association between 92 soluble inflammatory mediators (SIMs) and the steatosis grade, we made use of a cohort of 94 patients with chronic HCV infection who cleared HCV after direct-acting antiviral agent (DAA) treatment. Patients were classified into three groups according to their controlled attenuation parameter (CAP). CAP is associated with ALT, γ-GT and liver stiffness after HCV clearance. While stem cell factor (SCF) and tumor necrosis factor ligand superfamily member 12 (TWEAK) levels were significantly reduced in patients with CAP > 299 dB/m, the levels of fibroblast growth factor (FGF)-21 and interleukin-18 receptor 1 (IL-18R1) were higher in those patients at week 96 after virus clearance. These four markers also showed a linear correlation with CAP values. FGF-21 levels correlated with CAP only after HCV clearance. Taken together, these four biomarkers, namely SCF, TWEAK, FGF-21 and IL-18R1, are associated with CAP status after virus clearance. A potential role of these proteins in the pathogenesis of post-sustained viral response (SVR) nonalcoholic steatohepatitis requires further investigation.

Fibroblast Growth Factor 23: Potential Marker of Invisible Heart Damage in Diabetic Population.

Two-dimensional speckle-tracking echocardiography (2DSTE) detects myocardial dysfunction despite a preserved left ventricular ejection fraction. Fibroblast growth factor 23 (FGF23) has become a promising biomarker of cardiovascular risk. This study aimed to determine whether FGF23 may be used as a marker of myocardial damage among patients with diabetes mellitus type 2 (T2DM) and no previous history of myocardial infarction. The study enrolled 71 patients with a median age of 70 years. Laboratory data were analyzed retrospectively. Serum FGF23 levels were determined using a sandwich enzyme-linked immunosorbent assay. All patients underwent conventional echocardiography and 2DSTE. Baseline characteristics indicated that the median time elapsed since diagnosis with T2DM was 19 years. All subjects were divided into two groups according to left ventricular diastolic function. Individuals with confirmed left ventricular diastolic dysfunction had significantly lower levels of estimated glomerular filtration rate and higher values of hemoglobin A1c. Global circumferential strain (GCS) was reduced in the majority of patients. Only an epicardial GCS correlated significantly with the FGF23 concentration in all patients. The study indicates that a cardiac strain is a reliable tool for a subtle myocardial damage assessment. It is possible that FGF23 may become an early diagnostic marker of myocardial damage in patients with T2DM.

Short-Term Irisin Treatment Enhanced Neurotrophin Expression Differently in the Hippocampus and the Prefrontal Cortex of Young Mice.

As a result of physical exercise, muscle releases multiple exerkines, such as "irisin", which is thought to induce pro-cognitive and antidepressant effects. We recently demonstrated in young healthy mice the mitigation of depressive behaviors induced by consecutive 5 day irisin administration. To understand which molecular mechanisms might be involved in such effect, we here studied, in a group of mice previously submitted to a behavioral test of depression, the gene expression of neurotrophins and cytokines in the hippocampus and prefrontal cortex (PFC), two brain areas frequently investigated in the depression pathogenesis. We found significantly increased mRNA levels of nerve growth factor (NGF) and fibroblast growth factor 2 (FGF-2) in the hippocampus and brain-derived growth factor (BDNF) in the PFC. We did not detect a difference in the mRNA levels of interleukin 6 (IL-6) and IL-1β in both brain regions. Except for BDNF in the PFC, two-way ANOVA analysis did not reveal sex differences in the expression of the tested genes. Overall, our data evidenced a site-specific cerebral modulation of neurotrophins induced by irisin treatment in the hippocampus and the PFC, contributing to the search for new antidepressant treatments targeted at single depressive events with short-term protocols.

Promotion effect of FGF23 on osteopenia in congenital scoliosis through FGFr3/TNAP/OPN pathway.

Congenital scoliosis (CS) is a complex spinal malformation of unknown etiology with abnormal bone metabolism. Fibroblast growth factor 23 (FGF23), secreted by osteoblasts and osteocytes, can inhibit bone formation and mineralization. This research aims to investigate the relationship between CS and FGF23. We collected peripheral blood from two pairs of identical twins for methylation sequencing of the target region. FGF23 mRNA levels in the peripheral blood of CS patients and age-matched controls were measured. Receiver operator characteristic (ROC) curve analyses were conducted to evaluate the specificity and sensitivity of FGF23. The expression levels of FGF23 and its downstream factors fibroblast growth factor receptor 3 (FGFr3)/tissue non-specific alkaline phosphatase (TNAP)/osteopontin (OPN) in primary osteoblasts from CS patients (CS-Ob) and controls (CT-Ob) were detected. In addition, the osteogenic abilities of FGF23-knockdown or FGF23-overexpressing Ob were examined. DNA methylation of the FGF23 gene in CS patients was decreased compared to that of their identical twins, accompanied by increased mRNA levels. CS patients had increased peripheral blood FGF23 mRNA levels and decreased computed tomography (CT) values compared with controls. The FGF23 mRNA levels were negatively correlated with the CT value of the spine, and ROCs of FGF23 mRNA levels showed high sensitivity and specificity for CS. Additionally, significantly increased levels of FGF23, FGFr3, OPN, impaired osteogenic mineralization and lower TNAP levels were observed in CS-Ob. Moreover, FGF23 overexpression in CT-Ob increased FGFr3 and OPN levels and decreased TNAP levels, while FGF23 knockdown induced downregulation of FGFr3 and OPN but upregulation of TNAP in CS-Ob. Mineralization of CS-Ob was rescued after FGF23 knockdown. Our results suggested increased peripheral blood FGF23 levels, decreased bone mineral density in CS patients, and a good predictive ability of CS by peripheral blood FGF23 levels. FGF23 may contribute to osteopenia in CS patients through FGFr3/TNAP/OPN pathway.

Relationships between blood bone metabolic biomarkers and anemia in patients with chronic kidney disease

Introduction Blood bone metabolic biomarkers are noninvasive indices for evaluating metabolic bone diseases. We investigated the relationships between blood bone metabolic biomarkers and anemia in chronic kidney disease (CKD) patients and analyzed the effects of parathyroidectomy (PTX) on the above indices. Methods In this cross-sectional study, 100 healthy controls and 239 CKD patients, including 46 secondary hyperparathyroidism (SHPT) patients with PTX, were enrolled. Moreover, a prospective study was conducted in which 28 PTX patients were followed up. The degree of anemia was classified as mild, moderate, or severe based on the tertiles of hemoglobin (Hb) levels of the anemic CKD patients, with cutoff values of 83 g/L and 102 g/L. Bone metabolic biomarkers, including calcium (Ca), phosphorus (P), intact parathyroid hormone (iPTH), fibroblast growth factor 23 (FGF23), and α-klotho, were tested. Results The mean estimated glomerular filtration rate (eGFR) in CKD patients was 25.7 ± 36.0 ml/min/1.73 m2, and 84.10% of CKD patients had anemia. The baseline Hb levels in the mild, moderate, and severe anemia subgroups were 110.86 ± 5.99 g/L, 92.71 ± 5.96 g/L, and 67.38 ± 10.56 g/L, respectively. CKD patients had higher adjusted Ca, P, alkaline phosphatase (ALP), iPTH, and FGF23 levels and lower α-klotho levels than controls. Baseline adjusted Ca, P, iPTH, and α-klotho levels were associated with Hb levels in CKD patients. Blood adjusted Ca, P, and iPTH levels were correlated with anemia severity. After PTX (median interval: 6.88 months), anemia and high blood adjusted Ca, P, iPTH, and FGF23 levels were ameliorated, while α-klotho levels were increased. Conclusions Blood adjusted Ca, P, iPTH, and α-klotho levels were correlated with Hb levels in CKD patients. Correction of bone metabolic disorders may be a therapeutic strategy for anemia treatment.

Fibroblast growth factor 23, glucose homeostasis and incident diabetes: findings of two cohort studies.

The phosphate-regulating hormone fibroblast growth factor 23 (FGF23) has been linked to deregulations in glucose metabolism, but its role is insufficiently understood. This study investigates potential cross-talk between FGF23 and glucose homeostasis. First, we investigated the effect of glucose loading on plasma C-terminal FGF23 levels and its temporal relationship with changes in plasma phosphate in 45 overweight (BMI 25-30 kg/m2) subjects using time-lag analyses. Second, we studied cross-sectional associations of plasma C-terminal FGF23 levels with glucose homeostasis using multivariable linear regression in a population-based cohort. We also investigated associations of FGF23 with incident diabetes and obesity (BMI >30 kg/m2) in individuals without diabetes or obesity at baseline, respectively, using multivariable Cox regression analyses. Finally, we explored whether the association between FGF23 and diabetes depends on BMI. After glucose loading, changes in FGF23 preceded changes in plasma phosphate (Ptime-lag=0.04). In the population-based cohort (N=5482; mean age 52 yrs, 52% women, median FGF23 69 RU/mL), FGF23 was associated with plasma glucose (b 0.13[0.03-0.23], P=0.01), insulin (b 0.10[0.03-0.17], P<0.001), and proinsulin (b 0.06[0.02-0.10], P=0.01) at baseline. Upon longitudinal analyses, a higher baseline FGF23 was independently associated with development of diabetes (199 events (4%); fully adjusted HR 1.66[95% CI 1.06-2.60], P=0.03) and development of obesity (241 events (6%); fully adjusted HR 1.84[1.34-2.50], P<0.001). The association between FGF23 and incident diabetes lost significance after additional adjustment for BMI. Glucose loading has phosphate-independent effects on FGF23 and, vice versa, FGF23 is associated with glucose, insulin and proinsulin levels and obesity. These findings suggest cross-talk between FGF23 and glucose homeostasis, which may promote susceptibility to incident diabetes.

Short-Term Effects of a Therapeutic Diet on Biochemical Parameters in Hemodialysis Patients: A Randomized Crossover Trial

Although unhealthy diets exacerbate nutritional and metabolic derangements in patients with end-stage kidney disease (ESKD), how therapeutic diets that possess a variety of different dietary strategies acutely modify diverse biochemical parameters related to cardiovascular disease remains underexplored. Thirty-three adults with end-stage kidney disease undergoing thrice-weekly hemodialysis participated in a randomized crossover trial comparing a therapeutic diet with their usual diets for 7days, separated by a 4-week washout period. The therapeutic diet was characterized by adequate calorie and protein amounts, natural food ingredients with a low phosphorus-to-protein ratio, higher portions of plant-based food, and high fiber content. The primary outcome measure was the mean difference in the change-from-baseline intact fibroblast growth factor 23 (FGF23) level between the 2 diets. The other outcomes of interest included changes in mineral parameters, uremic toxins, and high-sensitivity C-reactive protein (hs-CRP) levels. Compared with the usual diet, the therapeutic diet lowered intact FGF23 levels (P=.001), decreased serum phosphate levels (P<.001), reduced intact parathyroid hormone (PTH) levels (P=.003), lowered C-terminal FGF23 levels (P=.03), increased serum calcium levels (P=.01), and tended to lower total indoxyl sulfate levels (P=.07) but had no significant effect on hs-CRP levels. Among these changes, reduction in serum phosphate level achieved in 2days, modifications of intact PTH and calcium levels in 5days, and reductions in intact and C-terminal FGF23 levels in 7days of therapeutic diet intervention. Within the 1-week intervention period, the dialysis-specific therapeutic diet rapidly reversed mineral abnormalities and tended to decrease total indoxyl sulfate levels in patients undergoing hemodialysis but had no effect on inflammation. Future studies to assess the long-term effects of such therapeutic diets are recommended.

Leucine supplementation in maternal high-fat diet alleviated adiposity and glucose intolerance of adult mice offspring fed a postweaning high-fat diet

BackgroundCombined maternal and postnatal high-fat (HF) diet intake predisposes offspring to metabolic dysregulation during adulthood. As the inhibitory effects of leucine consumption on obesity and metabolic disorders have been reported, the effects of maternal leucine supplementation on metabolic dysregulation in adult offspring were investigated.MethodsFemale mice were exposed to a control (C) or HF diet, with or without leucine (L) supplementation (1.5%, w/v), 3 weeks before mating, during pregnancy, and during lactation (C, CL, HF, and HFL). Male offspring were exposed to an HF diet for 12 weeks after weaning (C/HF, CL/HF, HF/HF, and HFL/HF). Serum biochemical parameters were determined for both the dams and offspring. Oral glucose tolerance test and qRT-PCR analysis were used to investigate metabolic dysregulation in the offspring.ResultsHFL dams exhibited higher relative adipose tissue weights than HF dams. Body weight, relative adipose tissue weight, and serum glucose levels were lower in the HFL/HF offspring than in the HF/HF offspring. Maternal leucine supplementation tended to alleviate glucose intolerance in the offspring of HF diet-fed dams. Additionally, mRNA levels of fibroblast growth factor 21 (FGF21), a hepatokine associated with glucose homeostasis, were higher in HFL/HF offspring than in HF/HF offspring and were negatively correlated with adiposity and serum glucose levels. The mRNA levels of genes encoding a FGF21 receptor complex, Fgf receptor 1 and klotho β, and its downstream targets, proliferator‐activated receptor‐γ co‐activator 1α and sirtuin 1, were higher in adipose tissues of the HFL/HF offspring than in those of the HF/HF offspring. Serum lipid peroxide levels were lower in HFL dams than in HF dams and positively correlated with body and adipose tissue weights of offspring.ConclusionsLeucine supplementation in HF diet-fed dams, but not in control diet-fed dams, resulted in an anti-obesity phenotype accompanied by glucose homeostasis in male offspring challenged with postnatal HF feeding. Activation of FGF21 signaling in the adipose tissue of offspring may be responsible for these beneficial effects of leucine.

Mild Chronic Kidney Disease Associated with Low Bone Formation and Decrease in Phosphate Transporters and Signaling Pathways Gene Expression.

The initial phases of molecular and cellular maladaptive bone responses in early chronic kidney disease (CKD) remain mostly unknown. We induced mild CKD in spontaneously hypertensive rats (SHR) by either causing arterial hypertension lasting six months (sham-operated rats, SO6) or in its' combination with 3/4 nephrectomy lasting two and six months (Nx2 and Nx6, respectively). Sham-operated SHRs (SO2) and Wistar Kyoto rats (WKY2) with a two-month follow-up served as controls. Animals were fed standard chow containing 0.6% phosphate. Upon follow-up completion in each animal, we measured creatinine clearance, urine albumin-to-creatinine ratio, renal interstitial fibrosis, inorganic phosphate (Pi) exchange, intact parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), Klotho, Dickkopf-1, sclerostin, and assessed bone response by static histomorphometry and gene expression profiles. The mild CKD groups had no increase in renal Pi excretion, FGF23, or PTH levels. Serum Pi, Dickkopf-1, and sclerostin were higher in Nx6. A decrease in trabecular bone area and osteocyte number was obvious in SO6. Nx2 and Nx6 had additionally lower osteoblast numbers. The decline in eroded perimeter, a resorption index, was only apparent in Nx6. Significant downregulation of genes related to Pi transport, MAPK, WNT, and BMP signaling accompanied histological alterations in Nx2 and Nx6. We found an association between mild CKD and histological and molecular features suggesting lower bone turnover, which occurred at normal levels of systemic Pi-regulating factors.

A potential link between fibroblast growth factor-23 and the progression of AKI to CKD

BackgroundPatients who recover from acute kidney injury (AKI) have a 25% increase in the risk of chronic kidney disease (CKD) and a 50% increase in mortality after a follow-up of approximately 10 years. Circulating FGF-23 increases significantly early in the development of AKI, is significantly elevated in patients with CKD and has become a major biomarker of poor clinical prognosis in CKD. However, the potential link between fibroblast growth factor-23 levels and the progression of AKI to CKD remains unclear.MethodSerum FGF-23 levels in AKI patients and ischaemia‒reperfusion injury (IRI) mice were detected with ELISA. Cultured HK2 cells were incubated with FGF-23 and PD173074, a blocker of FGFR, and then TGFβ/Smad and Wnt/β-catenin were examined with immunofluorescence and immunoblotting. Quantitative real-time polymerase chain reaction was used to detect the expression of COL1A1 and COL4A1. Histologic staining confirmed renal fibrosis.ResultsThe level of serum FGF-23 was significantly different between AKI patients and healthy controls (P < 0.01). Moreover, serum FGF-23 levels in the CKD progression group were significantly higher than those in the non-CKD progression group of AKI patients (P < 0.01). In the AKI-CKD mouse model, serum FGF-23 levels were increased, and renal fibrosis occurred; moreover, the protein expression of β-catenin and p-Smad3 was upregulated. PD173074 downregulated the expression of β-catenin and p-Smad3 and reduced fibrosis in both mice and HK2 cells.ConclusionThe increase in FGF-23 may be associated with the progression of AKI to CKD and may mediate renal fibrosis via TGF-β and Wnt/β-catenin activation.

445 The effects of dietary fiber based on fermentability and viscosity on phosphorus absorption and the gut microbiome in chronic kidney disease-mineral and bone disorder

OBJECTIVES/GOALS: To compare the effects of dietary fiber supplementation based on fermentability and viscosity on phosphorus fractional absorption and the gut microbiome in a rat model of chronic kidney disease-mineral and bone disorder (CKD-MBD). METHODS/STUDY POPULATION: 25-week-old Cy/+ male rats (CKD hereafter) will be randomly assigned to receive one of four fiber treatments (10% w/w each) based on fermentability and viscosity: 1) Cellulose (-fermentability, -viscosity), 2) inulin (+fermentability, -viscosity), 3) psyllium husk (-fermentability, +viscosity), or 4) pectin (+ fermentability, +viscosity). Diets will be formulated with a semipurified diet containing 0.7% phosphorus. Treatments will last for 10 weeks, and rats will be euthanized at 35 weeks of age, where animals have reached kidney failure. Intravenous and oral 33P will be used for intestinal phosphorus fractional absorption and cecal/fecal samples will be obtained at euthanasia for microbiome assessment using shotgun metagenomics. RESULTS/ANTICIPATED RESULTS: Our preliminary data show that fermentable dietary fiber (inulin) impacted phosphorus homeostasis by increasing the circulating levels of fibroblast growth factor-23 (a bone-derived hormone that increases phosphorus excretion in urine) and lowering circulating levels of phosphorus in the Cy/+ male rat model of progressive chronic kidney disease. We hypothesize that dietary fiber impacts phosphorus absorption in gut microbiome-dependent and independent mechanisms. For example, fermentable fiber enhances the production of short-chain fatty acids, lowering the intraluminal pH, and enhancing mineral solubility and absorption. Meanwhile, viscous fibers may encapsulate minerals limiting their absorption if these fibers are non-fermentable. DISCUSSION/SIGNIFICANCE: Hyperphosphatemia, or high circulating phosphorus, is a major factor in the pathogenesis of CKD-MBD. Treatment of hyperphosphatemia is focused on reducing intestinal absorption. However, available therapies vary in their efficacy and focus on phosphorus absorption in the small intestine, ignoring the possible impact of the large intestine.

PD03-01 FGF-23 PRODUCTION COUPLING WITH ALDOSTERONE AND PREDICTING CLINICAL OUTCOMES IN PRIMARY ALDOSTERONISM

You have accessJournal of UrologyCME1 Apr 2023PD03-01 FGF-23 PRODUCTION COUPLING WITH ALDOSTERONE AND PREDICTING CLINICAL OUTCOMES IN PRIMARY ALDOSTERONISM Jeff Chueh, Shuo-Meng Wang, VinCent Wu, and Kang-Yung Peng Jeff ChuehJeff Chueh More articles by this author , Shuo-Meng WangShuo-Meng Wang More articles by this author , VinCent WuVinCent Wu More articles by this author , and Kang-Yung PengKang-Yung Peng More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003220.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Higher fibroblast growth factor-23 (FGF-23) levels are associated with activating renin-angiotensin-aldosterone system (RAAS), more volume overload, and hypertension. The roles of FGF-23 in primary aldosteronism (PA) haven't been studied. METHODS: Unilateral PA (uPA) patients who underwent adrenalectomy were enrolled and followed for their clinical outcomes from Aug 15 to Jan 19. The FGF-23 expression in a rat osteoblast-like cell culture was evaluated after the addition of aldosterone. RESULTS: A total of 121 uPA patients & 69 matched essential hypertension (EH) controls were enrolled. The log [carboxyl-terminal FGF-23 (cFGF-23)] level was higher in uPA patients (p=0.001).] In Cox proportional hazard model, the preoperative Log [plasma cFGF-23]>1.98 was a risk factor for either all-cause mortality and cardiovascular or kidney events (HR, 4.01, p=0.038). Plasma cFGF-23 levels were increased in a nonlinear manner re: plasma aldosterone concentration (PAC). Log [plasma cFGF-23]>1.75 independently predicted post-op remission of hypertension (odds ratio (OR), 3.8, p=0.004). The plasma total FGF-23 level was significantly higher in PA patients (p<0.001), and it was significantly reduced post-op (p<0.001). When osteoblast-like UMR-106 cells were cultured with aldosterone, the cFGF-23 concentration in the culture medium was elevated (p=0.028), but it was abrogated after family with sequence similarity 20, member C (FAM20c) short hairpin RNA was added (p= 0.659). Docking experiments showed that aldosterone may bind to the potential drug binding pocket of FAM20c (Pdb: 5YH3; Figure 1A, B). CONCLUSIONS: Compared with EH controls, uPA patients had higher cFGF-23 levels--associated with a higher risk of cardiovascular composite outcomes, though such higher cFGF-23 levels predicted hypertension remission after adrenalectomy. Their total FGF-23 levels were significantly attenuated after adrenalectomy. An increase in cFGF-23 production among the uPA patients was secondary to increased cleavage of intact FGF-23 evidenced by higher FAM20c activity modulated by aldosterone. Source of Funding: Taiwan (NSC 101-2314-B-002-132-MY3, NSC100-2314-B-002-119, NSC 101-2314-B-002-085-MY3, MOST 104-2314-B-002 -125 -MY3; 111-2314-B-002-232-MY3) and NTUH 100-N1776, 101-M1953, 102-S2097 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e74 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jeff Chueh More articles by this author Shuo-Meng Wang More articles by this author VinCent Wu More articles by this author Kang-Yung Peng More articles by this author Expand All Advertisement PDF downloadLoading ...

Phosphate induces inflammation and exacerbates injury from cigarette smoke in the bronchial epithelium

An elevation in serum phosphate—also called hyperphosphatemia—is associated with reduced kidney function in chronic kidney disease (CKD). Reports show CKD patients are more likely to develop lung disease and have poorer kidney function that positively correlates with pulmonary obstruction. However, the underlying mechanisms are not well understood. Here, we report that two murine models of CKD, which both exhibit increased serum levels of phosphate and fibroblast growth factor (FGF) 23, a regulator of phosphate homeostasis, develop concomitant airway inflammation. Our in vitro studies point towards a similar increase of phosphate-induced inflammatory markers in human bronchial epithelial cells. FGF23 stimulation alone does not induce a proinflammatory response in the non-COPD bronchial epithelium and phosphate does not cause endogenous FGF23 release. Upregulation of the phosphate-induced proinflammatory cytokines is accompanied by activation of the extracellular-signal regulated kinase (ERK) pathway. Moreover, the addition of cigarette smoke extract (CSE) during phosphate treatments exacerbates inflammation as well as ERK activation, whereas co-treatment with FGF23 attenuates both the phosphate as well as the combined phosphate- and CS-induced inflammatory response, independent of ERK activation. Together, these data demonstrate a novel pathway that potentially explains pathological kidney-lung crosstalk with phosphate as a key mediator.

Evaluation of tumour necrosis factor alpha-stimulated gene-6 and fibroblast growth factor-2 levels in patients diagnosed with multi-system inflammatory syndrome in children.

Investigations are still ongoing about the pathophysiology of multi-system inflammatory syndrome in children, which can progress with serious morbidity and mortality after COVID-19 infection. In this study, we aimed to investigate whether fibroblast growth factor-2 and tumour necrosis factor alpha-stimulated gene-6 levels play a role in the diagnosis of the disease and on cardiac involvement. Twenty-three patients (11 girls, 12 boys) and 26 healthy controls (10 girls, 16 boys) were included in the study. The mean age of the patient and control group was 8.45 ± 2.43 and 10.73 ± 4.27 years, respectively. There was no difference between the fibroblast growth factor-2 and tumour necrosis factor alpha-stimulated gene-6 levels of the patient and control groups. When the patients with myocardial involvement in the patient group were compared with the patients without myocardial involvement in terms of fibroblast growth factor-2 and tumour necrosis factor alpha-stimulated gene-6 levels, no difference was found between these groups. The correlation of fibroblast growth factor-2 and tumour necrosis factor alpha-stimulated gene-6 levels with other laboratory parameters was investigated in the patient group. Fibroblast growth factor-2 was moderately inversely correlated with white blood cell count (r = -0.541, p = 0.008), absolute neutrophil count (r = -0.502, p = 0.015) and C-reactive protein (r = -0.528, p = 0.010). Fibroblast growth factor-2 was strongly inversely correlated with erythrocyte sedimentation rate (r = -0.694, p =<0.001). Our data show that fibroblast growth factor-2 and tumour necrosis factor alpha stimulated gene-6 do not provide sufficient information about diagnosis and cardiac involvement in multi-system inflammatory syndrome in children.

Craniosynostosis in Patients With X-Linked Hypophosphatemia: A Review.

Craniosynostosis is a rare condition of skull development, manifesting during fetal and early infant development, and is usually congenital. Craniosynostosis secondary to metabolic disorders, such as X-linked hypophosphatemia (XLH), is less common and is typically diagnosed later than congenital craniosynostosis. XLH is a rare, progressive, and lifelong hereditary phosphate-wasting disorder characterized by loss of function of the phosphate-regulating endopeptidase homologue, X-linked gene, which is associated with premature fusion of cranial sutures due to abnormal phosphate metabolism (hypophosphatemia) and altered bone mineralization or elevated levels of fibroblast growth factor 23. This targeted literature review of 38 articles seeks to provide an overview of craniosynostosis in individuals with XLH. The objectives of this review are to increase awareness of the prevalence, presentation, and diagnosis of craniosynostosis in XLH; examine the spectrum of craniosynostosis severity in XLH; discuss the management of craniosynostosis in those with XLH; recognize the complications for patients with XLH; and identify what is known about the burden of craniosynostosis for individuals with XLH. The presentation of craniosynostosis in individuals with XLH tends to manifest slightly later than congenital craniosynostosis and can vary in severity and appearance, making diagnosis difficult and resulting in inconsistent clinical outcomes. Consequently, craniosynostosis in patients with XLH is an underreported and potentially underrecognized condition. There have been no studies investigating the effects of craniosynostosis on the quality of life of people with XLH. Despite a growing awareness among researchers and experienced clinicians, there are still improvements to be made in general awareness and timely diagnosis of craniosynostosis in XLH. The XLH community would benefit from further study into the prevalence of craniosynostosis, the effect of XLH medical therapy on the development of craniosynostosis, and the effects of craniosynostosis on quality of life. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Association of Serum Fibroblast Growth Factor 23 and FGF23 Gene Variants with Chronic Kidney Disease in Patients with Type 2 Diabetes and Essential Hypertension

Fibroblast growth factor 23 (FGF23) gene variants could influence the production of FGF23 in subjects at risk for chronic kidney disease (CKD). Our purpose was to analyze the association of serum levels of FGF23 and two FGF23 gene variants with metabolic and renal function parameters in Mexican patients with Type 2 Diabetes (T2D) and/or essential hypertension (HTN). The study included 632 individuals diagnosed with T2D and/or HTN, of which 269 (43%) were diagnosed with CKD. FGF23 serum levels were determined and FGF23 gene variants rs11063112 and rs7955866 were genotyped. Genetic association analysis included binary and multivariate logistic regressions adjusted for age and sex. Patients with CKD were older, had higher systolic blood pressure, uric acid, and glucose levels than those without CKD. Also, patients with CKD had higher FGF23 levels (106 vs. 73 pg/mL p=0.003). No correlation of any gene variants with FGF23 levels was found, but minor allele for rs11063112 and haplotype rs11063112A-rs7955866A were associated with low probability of CKD (Odds Ratio [OR]=0.62 and 0.58, respectively). Conversely, the haplotype rs11063112T-rs7955866A was associated with increased FGF23 levels and risk for CKD (OR=6.90). In addition to the traditional risk factors, levels of FGF23 are higher in Mexican patients with diabetes and/or essential hypertension and CKD, compared to those without renal damage. In contrast, the two minor alleles of two variants of the FGF23 gene, rs11063112 and rs7955866, as well as the haplotype carrying these two alleles, were found to be protective against renal disease in this Mexican patients' sample.

Placebo-Controlled Study of Effects of Low-Energy Shockwave Therapy (LE-ESWT) on Erectile Tissue in a Diabetic Animal Model.

Low-energy extracorporeal shockwave therapy (LE-ESWT) has been shown to induce organ repair and neo-vascularization. The ability of LE-ESWT to improve erectile function in rodents as measured by improvements in intracavernosal pressure is well-established in various pathological situations. The underlying molecular mechanism are unclear and likely vary between different disorders, making rational drug design for synergetic effects with LE-ESWT difficult, without further research. In this placebo-controlled study, we aim to establish whether LE-ESWT can activate neovascularization biomarkers in diabetic tissues. Forty Wistar rats, aged 8 weeks, were randomly divided into 4 groups: 8 untreated controls, 12 controls that underwent LE-ESWT treatment, 8 controls with induced diabetes mellitus (DM) and 12 with DM underwent LE-ESWT treatment. DM was induced by streptozotocin. LE-ESWT treatment was performed with a Duolith SD1 machine (Storz), with a total amount of energy of 6.4 J per treatment. The rats received a total of three LE-ESWT treatments with 2-week intervals between treatments. Diabetic rats had significantly elevated blood glucose concentrations compared to control rats (P < 0.001) and experienced significant weight loss compared to controls (P < 0.001). Diabetic rats had elevated creatinine and urea and lower albumin (P < 0.001). Histologic analysis of penile tissue showed significant levels of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) expression in the LE-ESWT groups compared to controls (P< 0.01). LE-ESWT induces neo-angiogenesis as expressed by VEGF and FGF in erectile tissue in normal and diabetic rats.