scholarly journals FIBROBLAST GROWTH FACTOR 23 AND KLOTHO PROTEIN IN THE PATHOGENESIS OF SECONDARY HYPERPARATHYROIDISM

2013 ◽  
Vol 16 (3) ◽  
pp. 20-27
Author(s):  
A V Ilin ◽  
M I Arbuzova
Keyword(s):  
Secondary Hyperparathyroidism ◽  
Fibroblast Growth Factor 23 ◽  
Chronic Hemodialysis ◽  
Phosphorus Metabolism ◽  
Fibroblast Growth ◽  
Renal Phosphate Reabsorption ◽  
Calcium Phosphorus ◽  
Klotho Protein ◽  
Calcium And Phosphorus ◽  
Endocrine Axis

One of the main problems in patients with chronic kidney disease (CKD) is a disturbance of calcium-phosphorus metabolism, especially in chronic hemodialysis. Besides classical endocrine axis parathyroid-kidney, in recent years was established the existence of a new endocrine axis the bone-kidney, which gives a better explanation of the calcium and phosphorus metabolism abnormalities, pathophysiology of secondary hyperparathyroidism in CKD. FGF23 is a circulating factor synthesized in osteocytes. It inhibits renal phosphate reabsorption and activity of 1-alphahydroxylase. Anti-aging Klotho protein is a potent co-factor of FGF23. This review presents the mechanisms of the interaction of these elements of the newly discovered axis in normal settings and secondary hyperparathyroidism.

scholarly journals Fibroblast growth factor 23 and Klotho protein: assessment of the role in the development of secondary hyperparathyroidism in patients with various stages of chronic kidney disease

2021 ◽  
Vol 17 (5) ◽  
pp. 385-392
Author(s):  
N.V. Karlovich ◽  
T.V. Mokhort
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Secondary Hyperparathyroidism ◽  
Filtration Rate ◽  
Phosphorus Metabolism ◽  
Fibroblast Growth ◽  
Serum Concentrations ◽  
Calcium Phosphorus ◽  
Klotho Protein ◽  
Fgf 23

Background. Secondary hyperparathyroidism (SHPT) is universal complication of chronic kidney disease (CKD), the likelihood of which increases as renal function decreases. Currently, SHPT is considered in the context of mineral and bone disorders associated with CKD. Mineral and bone disorders associated with CKD include, in addition to SHPT, disorders of calcium-phosphorus metabolism, bone pathology and metastatic calcification, which determine poor outcomes of the disease. The purpose of the study was to evaluate the serum concentrations of fibroblast growth factor (FGF) 23 and Klotho protein in patients with various stages of CKD and their relationship with SHPT, vitamin D levels, and calcium-phosphorus metabolism in patients with varying degrees of decreased renal function. Materials and methods. Serum concentrations of FGF 23, Klotho protein, parathyroid hormone (PTH), 25(OH)D, calcium and phosphorus were evaluated in 229 patients with various stages of chronic kidney disease and in 40 people without signs of CKD. Results. It has been shown that individuals with CKD are characterized by overproduction of humoral phosphatonin FGF 23 and Klotho deficiency, which increase as renal failure worsens. A significant relationship was established between FGF 23 and the levels of PTH and blood phosphorus; Klotho protein — with the patient’s age and serum vitamin D. An early marker of disorders in the FGF 23-Klotho system is a decrease in the Klotho protein concentration, which occurs in the early stages of CKD and is aggravated with the progression of renal failure. A statistically significant overproduction of FGF 23 associated with secondary hyperparathyroidism was registered in patients with glomerular filtration rate less than 35 ml/min/1.73 m2. Conclusions. An early marker of disorders in the FGF 23-Klotho system is a decrease in the concentration of the Klotho protein, which occurs in the early stages of CKD and is aggravated with the progression of renal fai-lure. The relationship between Klotho deficiency and the formation of SHPT has not been found. As kidney function decreases, excess production of PTH and FGF 23 appears and increases, hyperphosphatemia progresses. This proves the pathogenetic relationship between the formation of SHPT and the overproduction of humoral phosphatonin FGF 23, since it is this glomerular filtration rate that determines the growth of PTH above the upper limit of the general population reference interval.

scholarly journals Fibroblast Growth Factor 23 and α-Klotho Protein Are Associated with Adverse Clinical Outcomes in Non-Dialysis CKD Patients

2020 ◽  
Vol 45 (6) ◽  
pp. 900-915
Author(s):  
Eleni Manou ◽  
Elias Thodis ◽  
Georgios Arsos ◽  
Ploumis Pasadakis ◽  
Stylianos Panagoutsos ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Primary Endpoint ◽  
Multivariate Regression ◽  
Fibroblast Growth Factor 23 ◽  
Regression Tree ◽  
Fibroblast Growth ◽  
Multivariate Regression Tree ◽  
Regression Tree Analysis ◽  
Klotho Protein ◽  
Fgf 23

<b><i>Background:</i></b> Fibroblast growth factor 23 (FGF-23) and α-Klotho protein appear to have an important role in the pathogenesis of CKD-mineral and bone disorders. The aim of this study was to investigate the association of FGF-23 and α-Klotho levels with adverse clinical outcomes in patients with non-dialysis CKD. <b><i>Materials and Methods:</i></b> We conducted a prospective cohort study, enrolling participants with non-dialysis CKD from a single center in Greece. At enrollment, glomerular filtration rate (GFR) was measured (mGFR) and plasma levels of carboxyl terminal FGF-23 (cFGF-23) and soluble α-Klotho (sKlotho) were determined by enzyme-linked immunoassay. Participants were followed for up to 5 years or until the occurrence of the primary endpoint of initiation of renal replacement therapy or death. Multivariate regression tree analysis was used to identify informative baseline parameters in order to categorize participants. Also, using median values of cFGF-23 and sKlotho, participants were categorized into 4 groups, in whom survival was compared using Kaplan-Meier and Cox regression analysis. <b><i>Results:</i></b> 128 participants were enrolled with a median mGFR of 41.5 mL/min/1.73 m<sup>2</sup> (IQR = 28.2). Baseline mGFR correlated with cFGF-23 and sKlotho (<i>r</i> = −0.54 and <i>r</i> = 0.49, respectively; <i>p</i> &#x3c; 0.0001 for both). cFGF-23 and sKlotho levels correlated negatively (<i>r</i> = −0.24, <i>p</i> = 0.006). Multivariate regression tree analysis resulted in 3 groups defined by cutoff values of mGFR (60.9 mL/min/1.73 m<sup>2</sup>) and phosphate (3.7 mg/dL). These groups correlated with CKD stage, cFGF-23, and sKlotho (<i>p</i> &#x3c; 0.0001 for all). During a median follow-up of 36 months (IQR = 22), 40 (31.2%) participants reached the primary endpoint (31 initiated renal replacement therapy, 9 died). Survival to primary endpoint differed among the 4 groups formed using median values of both biomarkers, with the low FGF-23/high Klotho and high FGF-23/low Klotho having the longest and shortest survival, respectively. High FGF-23/low Klotho group, compared to the opposite one, had a significantly elevated risk of the primary outcome (HR, 6.8; 95% CI, 2.3–19.6; <i>p</i> = 0.0004). <b><i>Conclusions:</i></b> In patients with CKD stages 1–5, the combination of higher cFGF-23 and lower sKlotho levels along with mGFR and serum phosphate was associated with adverse clinical outcomes. The utility of combinations of traditional and novel biomarkers to predict outcomes warrants further study.

scholarly journals Regulation of serum 1,25(OH)2Vitamin D3 levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4

2011 ◽  
Vol 301 (2) ◽  
pp. F371-F377 ◽  
Author(s):  
Jyothsna Gattineni ◽  
Katherine Twombley ◽  
Regina Goetz ◽  
Moosa Mohammadi ◽  
Michel Baum
Keyword(s):  
Vitamin D ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Serum Levels ◽  
Phosphate Transport ◽  
Fibroblast Growth ◽  
Wild Type ◽  
Baseline Serum ◽  
Renal Phosphate Reabsorption

Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone implicated in the pathogenesis of several hypophosphatemic disorders. FGF23 causes hypophosphatemia by decreasing the expression of sodium phosphate cotransporters (NaPi-2a and NaPi-2c) and decreasing serum 1,25(OH)2Vitamin D3 levels. We previously showed that FGFR1 is the predominant receptor for the hypophosphatemic actions of FGF23 by decreasing renal NaPi-2a and 2c expression while the receptors regulating 1,25(OH)2Vitamin D3 levels remained elusive. To determine the FGFRs regulating 1,25(OH)2Vitamin D3 levels, we studied FGFR3−/−FGFR4−/− mice as these mice have shortened life span and are growth retarded similar to FGF23−/− and Klotho−/− mice. Baseline serum 1,25(OH)2Vitamin D3 levels were elevated in the FGFR3−/−FGFR4−/− mice compared with wild-type mice (102.2 ± 14.8 vs. 266.0 ± 34.0 pmol/l; P = 0.001) as were the serum levels of FGF23. Administration of recombinant FGF23 had no effect on serum 1,25(OH)2Vitamin D3 in the FGFR3−/−FGFR4−/− mice (173.4 ± 32.7 vs. 219.7 ± 56.5 pmol/l; vehicle vs. FGF23) while it reduced serum 1,25(OH)2Vitamin D3 levels in wild-type mice. Administration of FGF23 to FGFR3−/−FGFR4−/− mice resulted in a decrease in serum parathyroid hormone (PTH) levels and an increase in serum phosphorus levels mediated by increased renal phosphate reabsorption. These data indicate that FGFR3 and 4 are the receptors that regulate serum 1,25(OH)2Vitamin D3 levels in response to FGF23. In addition, when 1,25(OH)2Vitamin D3 levels are not affected by FGF23, as in FGFR3−/−FGFR4−/− mice, a reduction in PTH can override the effects of FGF23 on renal phosphate transport.

P49 An unusual cause of transient migratory bone oedema: fibroblast growth factor-23 secreting a mesenchymal tumour

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Kerry Fisher ◽  
Sunil Melath ◽  
Sanjeev Patel
Keyword(s):  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth ◽  
Foot And Ankle ◽  
Mesenchymal Tumour ◽  
Hydroxyvitamin D ◽  
Renal Phosphate Reabsorption ◽  
History Of ◽  
25 Hydroxyvitamin D ◽  
Fgf 23 ◽  
Bone Oedema

Abstract Background Fibroblast growth factor-23 (FGF-23) is a phosphate regulator primarily expressed by osteocytes. Excess FGF-23 leads to decreased hydroxylation of 25-hydroxyvitamin D and poor renal phosphate reabsorption. This leads to hypophosphatemia and represents a rare cause of osteomalacia, resulting in bone oedema and stress fractures. Methods A 57-year-old man with known skin psoriasis presented with a two-year history of left foot and ankle pain. On examination, he had chronic dactylitis of the big toe and extra-articular features included skin psoriasis on the scalp, elbows, knees, and nail pitting. Serum inflammatory markers were normal, and autoimmune screens for RF, anti-CCP and HLA-B27 were negative. Bilateral foot and ankle X-rays showed no bony abnormality. This was diagnosed as likely psoriatic arthritis and MRI showed talar bone oedema, felt to be related to inflammatory arthritis. Symptoms settled well on non-steroidal anti-inflammatories. However, he presented with focal distal tibial swelling and pain, two months later. There was no history of trauma, Repeat MRI2 showed proximal migration of bone oedema with stress fractures of the left posterior talus and distal tibial metaphysis. Bloods tests showed low phosphate, elevated PTH, normal adjusted calcium, raised ALP and low 25-OH vitamin D. DEXA scan confirmed osteoporosis of the hip. The patient was commenced on bisphosphonate with 25-hydroxyvitamin D and phosphate supplementation. Despite this, the patient continued to have migratory joint pain affecting the ankle, hip and sacroiliac joints. Methotrexate was started for psoriasis and whilst his skin improved, his pain remained and further MRI showed left talar and right neck of femur insufficiency fractures. Results Although taking vitamin D3 supplementation, he remained hypophosphateamic 0.5mmol/L. Myeloma screen and PET FDG were normal. However, he was noted to have an increased fractional urinary phosphate excretion indicating poor renal phosphate reabsorption. One possible cause of this is elevated FGF-23, which was confirmed with FGF-23 assay (include levels and normal range). The patient underwent PET Ga-DOTATE imaging, utilising a tracer specific for somatostatin receptors found on neuroendocrine tumours. This showed a T9 pedicle lesion and a CT-guided biopsy confirmed a mesenchymal tumour as the cause of FGF-23 secretion, resulting in TBMO and insufficiency fractures. The patient has become asymptomatic on calcitriol and phosphate supplementation. He is now being considered for radiofrequency ablation therapy. Conclusion This case illustrates the need for a thorough investigation of symptomatic, treatment-refractory hypophosphataemia. Although mild hypophosphatemia could indicate adult-onset rickets, rarer causes such as FGF-23 secreting tumours should be considered. These tumours are notoriously difficult to locate; Ga-DOTATE PET is probably superior to other imaging modalities including FDG-PET in isolating mesenchymal tumours. Disclosures K. Fisher None. S. Melath None. S. Patel None.

scholarly journals Elevated Fibroblast Growth Factor 23 Concentration: Prediction of Mortality among Chronic Kidney Disease Patients

2015 ◽  
Vol 6 (1) ◽  
pp. 73-82 ◽  
Author(s):  
Shahanas Chathoth ◽  
Samir Al-Mueilo ◽  
Cyril Cyrus ◽  
Chittibabu Vatte ◽  
Awatif Al-Nafaie ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Growth Factor ◽  
Kidney Disease ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Control Group ◽  
Phosphorus Metabolism ◽  
Fibroblast Growth ◽  
Saudi Population ◽  
Fgf23 Level

Background: The osteocyte-derived hormone, fibroblast growth factor 23 (FGF23), regulates the phosphorus metabolism and suppresses 1,25-dihydroxyvitamin D production, thereby mitigating hyperphosphatemia in patients with renal disorders. An elevated FGF23 level is suggested to be an early biomarker of altered phosphorus metabolism in the initial stages of chronic kidney disease (CKD) and acts as a strong predictor of mortality in dialysis patients. In the Saudi population, there is no report on the FGF23 level in CKD patients to date. This study aims to estimate the plasma FGF23 levels in the Saudi population and to correlate it with its clinical manifestations in order to ascertain its role in the pathogenesis of CKD patients. Methods: The FGF23 level in the plasma samples was determined using ELISA in a diverse cohort of 89 cases with stage 3-5 CKD and 100 healthy subjects. The plasma FGF23 level was correlated with other biochemical parameters. Results: The results revealed that the FGF23 level was markedly elevated among CKD patients compared to the control group, and a significant inverse correlation was observed between the FGF23 level and glomerular filtration rate. FGF23 elevation was approximately 40-fold among stage 5 patients compared to the control, while the elevation of phosphate, parathyroid hormone (PTH) and alkaline phosphatase was 2-, 3- and 8-fold in this stage, respectively. Conclusion: Elevated FGF23 levels may have a strong correlation with the disease pathogenesis. In addition, FGF23 might be a future therapeutic target to intervene against the progression of CKD as well as to increase patient survivability.

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