Crosstalk between FGF23- and angiotensin II-mediated Ca signaling in pathological cardiac hypertrophy.
Mhatre Ketaki N,Wakula Paulina,Klein Oliver,Bisping Egbert,Völkl Jakob,Pieske Burkert,Heinzel Frank R
Cellular and molecular life sciences : CMLS
Heart failure (HF) manifestation and progression are driven by systemic activation of neuroendocrine signaling cascades, such as the renin-angiotensin aldosterone system (RAAS). Fibroblast growth factor 23 (FGF23), an endocrine hormone, is linked to HF and cardiovascular mortality. It is also a mediator of left-ventricular hypertrophy (LVH). In vivo, high circulating levels of FGF23 are associated with an altered systemic RAAS response. FGF23 is proposed to trigger pathological signaling mediated by Ca-regulated transcriptional pathways. In the present study, we investigated Ca-dependent signaling of FGF23 in ventricular cardiomyocytes and its association with angiotensin II (ATII). In neonatal rat ventricular myocytes (NRVMs), both ATII and FGF23 induced hypertrophy as observed by an increase in cell area and hypertrophic gene expression. Furthermore, FGF23 activates nuclear Ca-regulated CaMKII-HDAC4 pathway, similar to ATII. In addition to a global increase in cytoplasmic Ca, FGF23, like ATII, induced inositol 1, 4, 5-triphosphate (IP3)-induced Ca release from the nucleoplasmic Ca store, associated with cellular hypertrophy. Interestingly, ATII receptor antagonist, losartan, significantly attenuated FGF23-induced changes in Ca homeostasis and cellular hypertrophy suggesting an involvement of ATII receptor-mediated signaling. In addition, application of FGF23 increased intracellular expression of ATII peptide and its secretion in NRVMs, confirming the participation of ATII. In conclusion, FGF23 and ATII share a common mechanism of IP3-nuclear Ca-dependent cardiomyocyte hypertrophy. FGF23-mediated cellular hypertrophy is associated with increased production and secretion of ATII by cardiomyocytes. These findings indicate a pathophysiological role of the cellular angiotensin system in FGF23-induced hypertrophy in ventricular cardiomyocytes.
Pre-operative level of FGF23 predicts severe acute kidney injury after heart surgery in children.
Volovelsky Oded,Terrell Tara C,Swain Hayley,Bennett Michael R,Cooper David S,Goldstein Stuart L
Pediatric nephrology (Berlin, Germany)
BACKGROUND:Early detection of acute kidney injury (AKI) after cardiac surgery has improved recently with the discovery and validation of novel urinary biomarkers. However, objective tools to predict the risk of AKI before the insult are still missing. We tested the hypothesis that pre-operative serum fibroblast growth factor 23 (FGF23) concentrations would be elevated in children who develop AKI after heart surgery with cardiopulmonary bypass (CPB). We also compared post-operative FGF23 concentrations to other biomarkers for early detection of AKI. METHODS:Blood and urine samples were collected in a prospective observational study from 83 children with congenital heart disease. Severe AKI (sAKI) development (KDIGO stages II-III) in the first seven days after surgery was the primary outcome. RESULTS:Thirty of 76 (39.5%) and 11/76 (14.5%) of patients developed AKI and sAKI, respectively. Pre-operative serum creatinine, cystatin C, and urine biomarker concentrations did not differ between sAKI patients and controls. Pre-operative serum FGF23 levels were higher in patients who developed sAKI (median [IQR] value of 819 RU/ml [397.7, 1196.8] vs. 324.3 RU/ml [124.6, 679.8] (p = 0.02). FGF23 12-24 h after the termination of CPB was also associated with sAKI in the first week after surgery (498 RU/ml [226, 928] vs. 1435 RU/ml [831, 12,996]). CONCLUSIONS:Pre- and post-operative FGF23 levels are higher in children who develop sAKI after cardiac surgery. We suggest FGF23 may be able to detect sub-clinical kidney injury and can be used with demographic AKI risk factors to enhance post-operative sAKI risk prediction.
Non-renal-Related Mechanisms of FGF23 Pathophysiology.
Hanudel Mark R,Laster Marciana,Salusky Isidro B
Current osteoporosis reports
PURPOSE OF REVIEW:We will review non-renal-related mechanisms of fibroblast growth factor 23 (FGF23) pathophysiology. RECENT FINDINGS:FGF23 production and metabolism may be affected by many bone, mineral, and kidney factors. However, it has recently been demonstrated that other factors, such as iron status, erythropoietin, and inflammation, also affect FGF23 production and metabolism. As these non-mineral factors are especially relevant in the setting of chronic kidney disease (CKD), they may represent emerging determinants of CKD-associated elevated FGF23 levels. Moreover, FGF23 itself may promote anemia and inflammation, thus contributing to the multifactorial etiologies of these CKD-associated comorbidities. CKD-relevant, non-mineral-related, bidirectional relationships exist between FGF23 and anemia, and between FGF23 and inflammation. Iron deficiency, anemia, and inflammation affect FGF23 production and metabolism, and FGF23 itself may contribute to anemia and inflammation, highlighting complex interactions that may affect aspects of CKD pathogenesis and treatment.
FGF23 and Fetuin-A Interaction in the Liver and in the Circulation.
Mattinzoli Deborah,Ikehata Masami,Tsugawa Koji,Alfieri Carlo M,Dongiovanni Paola,Trombetta Elena,Valenti Luca,Puliti Aldamaria,Lazzari Lorenza,Messa Piergiorgio
International journal of biological sciences
Recently it has been demonstrated that Fetuin-A, an anti-inflammatory protein synthesized by the liver, is produced also in bone by an FGF23-regulated pathway. FGF23 has been also demonstrated to induce inflammatory cytokine production in the liver. This study aimed to explore if FGF23 plays a role in the Fetuin-A production in the liver cells too and the possible relationships with FGF23 pro-inflammatory effects. FGF23 and Fetuin-A were studied in liver, kidney and in plasma with immunochemistry, immunoprecipitation, western blot, chromatin immunoprecipitation, duolink, ELISA, qrtPCR methodology. FGF23 is produced, but not secreted by the liver cells. In hepatocytes and circulation, FGF23 was present only strictly linked to Fetuin-A, while Fetuin-A was found also in unbounded form. No link was observed in the kidney. FGF23 up to 600 pg/ml stimulates, while, at higher concentrations, reduces Fetuin-A expression. Notably, overall the range of concentrations, FGF23 stimulates Fetuin-A promoter, TNFα and IL6 expression. In the nucleus, FGF23 seems to act as a direct transcription factor of Fetuin-A promoter. These results suggest that FGF23 played a direct regulatory role in Fetuin-A expression in liver cells with a biphasic effect: Fetuin-A progressively increases when FGF23 increases up to 400-600 pg/mL, and declines at higher FGF23 concentrations. These results lead us to hypothesize: a) a possible epigenetic post-transcriptional regulation; b) a possible counter-regulatory effect of FGF23 induced inflammatory cytokines (TNFα/ NF-κB mechanism). This study could add an additional key for the interpretation of the possible mechanisms linking FGF23, Fetuin-A and inflammation in CKD patients and suggests a role for FGF23 as transcription factor.
FGF23 modulates the effects of erythropoietin on gene expression in renal epithelial cells.
Yashiro Mitsuru,Ohya Masaki,Mima Toru,Ueda Yumi,Nakashima Yuri,Kawakami Kazuki,Ishizawa Yohei,Yamamoto Shuto,Kobayashi Sou,Yano Takurou,Tanaka Yusuke,Okuda Kouji,Sonou Tomohiro,Shoshihara Tomohiro,Iwashita Yuko,Iwashita Yu,Tatsuta Kouichi,Matoba Ryo,Negi Shigeo,Shigematsu Takashi
International journal of nephrology and renovascular disease
Background:FGF23 plays an important role in calcium-phosphorus metabolism. Other roles of FGF23 have recently been reported, such as commitment to myocardium enlargement and immunological roles in the spleen. In this study, we aimed to identify the roles of FGF23 in the kidneys other than calcium-phosphorus metabolism. Methods:DNA microarrays and bioinformatics tools were used to analyze gene expression in mIMCD3 mouse renal tubule cells following treatment with FGF23, erythropoietin and/or an inhibitor of ERK. Results:Three protein-coding genes were upregulated and 12 were downregulated in response to FGF23. Following bioinformatics analysis of these genes, PPARγ and STAT3 were identified as candidate transcript factors for mediating their upregulation, and STAT1 as a candidate for mediating their downregulation. Because STAT1 and STAT3 also mediate erythropoietin signaling, we investigated whether FGF23 and erythropoietin might show interactive effects in these cells. Of the 15 genes regulated by FGF23, 11 were upregulated by erythropoietin; 10 of these were downregulated following cotreatment with FGF23. Inhibition of ERK, an intracellular mediator of FGF23, reversed the effects of FGF23. However, FGF23 did not influence STAT1 phosphorylation, suggesting that it impinges on erythropoietin signaling through other mechanisms. Conclusion:Our results suggest cross talk between erythropoietin and FGF23 signaling in the regulation of renal epithelial cells.
Phosphate-dependent FGF23 secretion is modulated by PiT2/Slc20a2.
Bon Nina,Frangi Giulia,Sourice Sophie,Guicheux Jérôme,Beck-Cormier Sarah,Beck Laurent
OBJECTIVE:The canonical role of the bone-derived fibroblast growth factor 23 (Fgf23) is to regulate the serum inorganic phosphate (Pi) level. As part of a feedback loop, serum Pi levels control Fgf23 secretion through undefined mechanisms. We recently showed in vitro that the two high-affinity Na-Pi co-transporters PiT1/Slc20a1 and PiT2/Slc20a2 were required for mediating Pi-dependent signaling. Here, we addressed the contribution of PiT1 and PiT2 to the regulation of Fgf23 secretion. METHODS:To this aim, we used PiT2 KO and DMP1Cre; PiT1 fed Pi-modified diets, as well as ex vivo isolated long bone shafts. Fgf23 secretion and expression of Pi homeostasis-related genes were assessed. RESULTS:In vivo, PiT2 KO mice responded inappropriately to low-Pi diets, displaying abnormally normal serum levels of intact Fgf23. Despite the high iFgf23 level, serum Pi levels remained unaffected, an effect that may relate to lower αKlotho expression in the kidney. Moreover, consistent with a role of PiT2 as a possible endocrine Pi sensor, the iFGF23/cFGF23 ratios were suppressed in PiT2 KO mice, irrespective of the Pi loads. While deletion of PiT1 in osteocytes using the DMP1-Cre mice was inefficient, adenovirus-mediated deletion of PiT1 in isolated long bone shafts suggested that PiT1 does not contribute to Pi-dependent regulation of Fgf23 secretion. In contrast, using isolated bone shafts from PiT2 KO mice, we showed that PiT2 was necessary for the appropriate Pi-dependent secretion of Fgf23, independently from possible endocrine regulatory loops. CONCLUSIONS:Our data provide initial mechanistic insights underlying the Pi-dependent regulation of Fgf23 secretion in identifying PiT2 as a potential player in this process, at least in high Pi conditions. Targeting PiT2, therefore, could improve excess FGF23 in hyperphosphatemic conditions such as chronic kidney disease.
The participation of fibroblast growth factor 23 (FGF23) in the progression of osteoporosis via JAK/STAT pathway.
Xu Lijun,Zhang Lixia,Zhang Huijuan,Yang Zaigang,Qi Lei,Wang Yurong,Ren Shuxin
Journal of cellular biochemistry
Osteoporosis (OP) is a major skeletal disorder for the old man. The fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced by osteoblasts and osteocytes. However, the regulatory mechanisms of FGF23 in the progression of osteoporosis remain poorly understood. This study aims to explore the downstream regulating pathway of FGF23 in postmenopausal osteoporosis. The rat model of osteoporosis was established through ovariectomy (OVX). The investigation demonstrated that the serum levels of FGF23 and the phosphorylation levels of JAK2, STAT1, and STAT3 were up-regulated in the OVX + NVP-BGJ398 group while were down-regulated in the OVX + Anti-FGF23 group than that in the OVX group. Moreover, the JAK2/STAT1/3 inhibitor, AG490 promoted the OVX-induced increase in the osteocalcin, ALP, BALP, TRAP, and CTX-I levels. Besides, AG490 enhanced cartilage lesions and increased TUNEL-positive chondrocytes in the OVX group. In addition, higher protein expression of MMP-1 and MMP-13 and lower expression of COX-II were observed in the OVX + AG490 group than that in the OVX group. Our findings suggested that FGF23 was involved in the progression of osteoporosis via the JAK/STAT signaling pathway.
FGF23 Actions on Target Tissues-With and Without Klotho.
Richter Beatrice,Faul Christian
Frontiers in endocrinology
Fibroblast growth factor (FGF) 23 is a phosphaturic hormone whose physiologic actions on target tissues are mediated by FGF receptors (FGFR) and klotho, which functions as a co-receptor that increases the binding affinity of FGF23 for FGFRs. By stimulating FGFR/klotho complexes in the kidney and parathyroid gland, FGF23 reduces renal phosphate uptake and secretion of parathyroid hormone, respectively, thereby acting as a key regulator of phosphate metabolism. Recently, it has been shown that FGF23 can also target cell types that lack klotho. This unconventional signaling event occurs in an FGFR-dependent manner, but involves other downstream signaling pathways than in "classic" klotho-expressing target organs. It appears that klotho-independent signaling mechanisms are only activated in the presence of high FGF23 concentrations and result in pathologic cellular changes. Therefore, it has been postulated that massive elevations in circulating levels of FGF23, as found in patients with chronic kidney disease, contribute to associated pathologies by targeting cells and tissues that lack klotho. This includes the induction of cardiac hypertrophy and fibrosis, the elevation of inflammatory cytokine expression in the liver, and the inhibition of neutrophil recruitment. Here, we describe the signaling and cellular events that are caused by FGF23 in tissues lacking klotho, and we discuss FGF23's potential role as a hormone with widespread pathologic actions. Since the soluble form of klotho can function as a circulating co-receptor for FGF23, we also discuss the potential inhibitory effects of soluble klotho on FGF23-mediated signaling which might-at least partially-underlie the pleiotropic tissue-protective functions of klotho.
FGF23 in Cardiovascular Disease: Innocent Bystander or Active Mediator?
Stöhr Robert,Schuh Alexander,Heine Gunnar H,Brandenburg Vincent
Frontiers in endocrinology
Fibroblast growth factor-23 (FGF23) is a mainly osteocytic hormone which increases renal phosphate excretion and reduces calcitriol synthesis. These renal actions are mediated via alpha-klotho as the obligate co-receptor. Beyond these canonical "mineral metabolism" actions, FGF23 has been identified as an independent marker for cardiovascular risk in various patient populations. Previous research has linked elevated FGF23 predominantly to left-ventricular dysfunction and consecutive morbidity and mortality. Moreover, some experimental data suggest FGF23 as a direct and causal stimulator for cardiac hypertrophy via specific myocardial FGF23-receptor activation, independent from alpha-klotho. This hypothesis offers fascinating prospects in terms of therapeutic interventions, specifically in patients with chronic kidney disease (CKD) in whom the FGF23 system is strongly stimulated and in whom left-ventricular dysfunction is a major disease burden. However, novel data challenges the previous stand-alone hypothesis about a one-way road which guides unidirectionally skeletal FGF23 toward cardiotoxic effects. In fact, recent data point toward local myocardial production and release of FGF23 in cases where (acute) myocardial damage occurs. The effects of this local production and the physiological meaning are under current examination. Moreover, epidemiologic studies suggest that high FGF-23 may follow, rather than induce, myocardial disease in certain conditions. In summary, while FGF23 is an interesting link between mineral metabolism and cardiac function underlining the meaning of the bone-heart axis, more research is needed before therapeutic interventions may be considered.
Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia.
Agoro Rafiou,Montagna Anna,Goetz Regina,Aligbe Onyedikachi,Singh Gurinder,Coe Lindsay M,Mohammadi Moosa,Rivella Stefano,Sitara Despina
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Severe anemia and iron deficiency are common complications in chronic kidney disease. The cause of renal anemia is multifactorial and includes decreased erythropoietin (Epo) production, iron deficiency, and inflammation, and it is currently treated with injections of synthetic Epo. However, the use of recombinant Epo has several adverse effects. We previously reported that high fibroblast growth factor 23 (FGF23) levels in mice are associated with decreased red blood cell production, whereas genetic inactivation of Fgf23 results in expansion of the erythroid lineage. The present study is the first to show that high FGF23 levels in a mouse model of renal failure contribute to renal anemia, and inhibiting FGF23 signaling stimulates erythropoiesis and abolishes anemia and iron deficiency. Moreover, we show that inhibition of FGF23 signaling significantly decreases erythroid cell apoptosis and influences the commitment of hematopoietic stem cells toward the erythroid linage. Furthermore, we show that blocking FGF23 signaling attenuates inflammation, resulting in increased serum iron and ferritin levels. Our data clearly demonstrate that elevated FGF23 is a causative factor in the development of renal anemia and iron deficiency, and importantly, blocking FGF23 signaling represents a novel approach to stimulate erythropoiesis and possibly improve survival for millions of chronic kidney disease patients worldwide.-Agoro, R., Montagna, A., Goetz, R., Aligbe, O., Singh, G., Coe, L. M., Mohammadi, M., Rivella, S., Sitara, D. Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia.
Is FGF23 effective on insulin resistance in individuals with metabolic syndrome?
Sit Dede,Tanrıverdi Ender,Kayabasi Hasan,Erdem Muslum,Sari Hakan
Hormone molecular biology and clinical investigation
Purpose Metabolic syndrome (MetS) is a polymetabolic syndrome has high morbidity and mortality rates. Insulin resistance (IR) plays a key role in the increasing frequency of this situation and has been cited as being an important etiologic factor in MetS. In this study, the relationship between IR and fibroblast growth factor-23 (FGF23), was investigated in a population with MetS. Materials and methods Forty patients with diagnosis of MetS and 40 healthy volunteers with an equal number of males and females were included in the study and classified as patient group and control group. Blood samples were obtained after 12-h fasting period to study FGF23 and other parameters. MetS, defined according to the International Diabetes Federation (IDF) guidelines, FGF23 was studied by Enzyme-Linked ImmunoSorbent Assay (ELISA) method and IR was calculated using the homeostatic model assessment-insulin resistance (HOMA-IR) formula. Results There was a statistically significant difference in HOMA-IR between the patient and control group as expected, while levels of FGF23 were similar. According to gender, levels of FGF23 was statistically significantly higher in male patients compared with controls (p = 0.037). A relationship was not detected between HOMA-IR and FGF23 in the correlation analysis. Conclusion Although there are many studies suggesting the correlation between FGF23 and IR in different populations, we did not find any statistically significant relationship between IR and FGF23 levels in MetS in this study.
Erythropoietin stimulates fibroblast growth factor 23 (FGF23) in mice and men.
Daryadel Arezoo,Bettoni Carla,Haider Thomas,Imenez Silva Pedro H,Schnitzbauer Udo,Pastor-Arroyo Eva Maria,Wenger Roland H,Gassmann Max,Wagner Carsten A
Pflugers Archiv : European journal of physiology
Fibroblast growth factor 23 (FGF23) is a major endocrine regulator of phosphate and 1,25 (OH) vitamin D metabolism and is mainly produced by osteocytes. Its production is upregulated by a variety of factors including 1,25 (OH) vitamin D, high dietary phosphate intake, and parathyroid hormone (PTH). Recently, iron deficiency and hypoxia have been suggested as additional regulators of FGF23 and a role of erythropoietin (EPO) was shown. However, the regulation of FGF23 by EPO and the impact on phosphate and 1,25(OH) vitamin D are not completely understood. Here, we demonstrate that acute administration of recombinant human EPO (rhEPO) to healthy humans increases the C-terminal fragment of FGF23 (C-terminal FGF23) but not intact FGF23 (iFGF23). In mice, rhEPO stimulates acutely (24 h) C-terminal FGF23 but iFGF23 only after 4 days without effects on PTH and plasma phosphate. 1,25 (OH) D levels and αklotho expression in the kidney decrease after 4 days. rhEPO induced FGF23 mRNA in bone marrow but not in bone, with increased staining of FGF23 in CD71 erythroid precursors in bone marrow. Chronic elevation of EPO in transgenic mice increases iFGF23. Finally, acute injections of recombinant FGF23 reduced renal EPO mRNA expression. Our data demonstrate stimulation of FGF23 levels in mice which impacts mostly on 1,25 (OH) vitamin D levels and metabolism. In humans, EPO is mostly associated with the C-terminal fragment of FGF23; in mice, EPO has a time-dependent effect on both FGF23 forms. EPO and FGF23 may form a feedback loop controlling and linking erythropoiesis and mineral metabolism.
FGF23 impairs peripheral microvascular function in renal failure.
Verkaik Melissa,Juni Rio P,van Loon Ellen P M,van Poelgeest Erik M,Kwekkeboom Rick F J,Gam Zeineb,Richards William G,Ter Wee Pieter M,Hoenderop Joost G,Eringa Etto C,Vervloet Marc G,
American journal of physiology. Heart and circulatory physiology
Cardiovascular diseases account for ~50% of mortality in patients with chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) is independently associated with endothelial dysfunction and cardiovascular mortality. We hypothesized that CKD impairs microvascular endothelial function and that this can be attributed to FGF23. Mice were subjected to partial nephrectomy (5/6Nx) or sham surgery. To evaluate the functional role of FGF23, non-CKD mice received FGF23 injections and CKD mice received FGF23-blocking antibodies after 5/6Nx surgery. To examine microvascular function, myocardial perfusion in vivo and vascular function of gracilis resistance arteries ex vivo were assessed in mice. 5/6Nx surgery blunted ex vivo vasodilator responses to acetylcholine, whereas responses to sodium nitroprusside or endothelin were normal. In vivo FGF23 injections in non-CKD mice mimicked this endothelial defect, and FGF23 antibodies in 5/6Nx mice prevented endothelial dysfunction. Stimulation of microvascular endothelial cells with FGF23 in vitro did not induce ERK phosphorylation. Increased plasma asymmetric dimethylarginine concentrations were increased by FGF23 and strongly correlated with endothelial dysfunction. Increased FGF23 concentration did not mimic impaired endothelial function in the myocardium of 5/6Nx mice. In conclusion, impaired peripheral endothelium-dependent vasodilatation in 5/6Nx mice is mediated by FGF23 and can be prevented by blocking FGF23. These data corroborate FGF23 as an important target to combat cardiovascular disease in CKD. NEW & NOTEWORTHY In the present study, we provide the first evidence that fibroblast growth factor 23 (FGF23) is a cause of peripheral endothelial dysfunction in a model of early chronic kidney disease (CKD) and that endothelial dysfunction in CKD can be prevented by blockade of FGF23. This pathological effect on endothelial cells was induced by long-term exposure of physiological levels of FGF23. Mechanistically, increased plasma asymmetric dimethylarginine concentrations were strongly associated with this endothelial dysfunction in CKD and were increased by FGF23.
C-terminal and intact FGF23 in critical illness and their associations with acute kidney injury and in-hospital mortality.
Rygasiewicz Karolina,Hryszko Tomasz,Siemiatkowski Andrzej,Brzosko Szymon,Rydzewska-Rosolowska Alicja,Naumnik Beata
BACKGROUND:FGF23 proved its value in prognostication of cardiovascular events and mortality among renal patients and general population. Limited data exist whether FGF23 may have any use in prediction of negative outcomes among critically ill patients admitted to intensive care unit (ICU). METHODS:Single center cohort study performed among patients admitted to ICU. The primary exposure was FGF23 plasma concentration measured within 24 h of ICU admission. The primary outcome was incident Acute Kidney Injury (AKI) and in-hospital mortality during the ICU stay. RESULTS:The study enrolled 79 patients admitted to ICU. C-terminal FGF23 (cFGF23) but not intact FGF23 (iFGF23) concentration was significantly elevated in patients, who acquired AKI and non-survivors (p < .001). ROC analysis of cFGF23 yielded an AUC of 0.81 and 0.85 for prediction of incident AKI and death during ICU stay, respectively. Multivariate analysis showed higher odds for AKI (OR 1.80; 95% CI 1.10-2.96) and in-hospital mortality (OR 2.85; 95% CI 1.60-5.06) for one unit increase of log transformed cFGF23. CONCLUSIONS:cFGF23 measurement may serve as a novel biomarker for incident AKI and death among critically ill patients.
Effect of Cholecalciferol therapy on serum FGF in vitamin D deficient patients: a randomized clinical trial.
Kamelian T,Saki F,Jeddi M,Dabbaghmanesh M H,Omrani G H R
Journal of endocrinological investigation
INTRODUCTION:Fibroblast growth factor-23 plays an important role in regulating systemic phosphate homeostasis, and vitamin D metabolism. However, the effect of Cholecalciferol therapy on FGF serum level in patients with vitamin D deficiency has not been studied, yet. MATERIALS AND METHODS:This is a double-blind, randomized clinical trial on 119 vitamin D deficient patients in 2016. Biochemical variables of treatment and placebo groups were analyzed after 12 weeks of 50,000 IU of Cholecalciferol vs. placebo therapy once a week, by SPSS18. RESULTS:After Cholecalciferol therapy, delta of serum PTH in treatment group was less than the controls (P < 0.001). However, delta values of serum 25(OH)D, 1,25(OH)D and FGF in vitamin D treated group were more than the placebo-treated ones (P < 0.001, P = 0.002, and P = 0.04, respectively). Moreover, FGF serum level in treatment group was associated with serum calcium (P = 0.005, r = -0.256), and serum 1,25(OH)D (P < 0.001, r = 0.529). CONCLUSIONS:We propose that in these patients 1,25(OH)D has a positive association with serum FGF, and hypostasized that serum calcium might be a down regulator of serum FGF.
The FGF23-Klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease-a prospective cohort study.
Tranæus Lindblad Ylva,Olauson Hannes,Vavilis Georgios,Hammar Ulf,Herthelius Maria,Axelsson Jonas,Bárány Peter
Pediatric nephrology (Berlin, Germany)
BACKGROUND:Chronic kidney disease-associated mineral bone disorder (CKD-MBD) is common in pediatric kidney disease patients and a risk factor for future cardiovascular disease (CVD). Fibroblast growth factor-23 (FGF23) and Klotho are novel key players in CKD-MBD, and has been suggested to be involved in the development of CVD. METHODS:This prospective cohort study included 74 pediatric patients; 31 with CKD (age range 0.8-18.8 years, glomerular filtration rate (GFR) range 9-68 mL/min/1.73 m) and 43 transplanted patients (CKD-T; age range 3.3-17.7 years, GFR range 10-99 mL/min/1.73 m) examined annually for 3 years. We assessed longitudinal patterns and predictors of FGF23 and soluble Klotho, as well as associations to cardiac remodeling and function using echocardiographic pulse wave Doppler (PWD) and color-coded tissue Doppler imaging (cc-TDI). RESULTS:The prevalence of high FGF23 levels (≥95th percentile) was 60% in CKD and 42% in CKD-T patients, despite a low prevalence of hyperphosphatemia and normal Klotho levels. Low GFR at baseline was a predictor for high mean log FGF23 during follow-up in CKD and CKD-T patients (β = -0.2, p < 0.001). A high log FGF23 z-score longitudinally was borderline significantly associated with elevated left ventricular mass index (LVMI) in CKD patients (β = 1.8, p = 0.06). In addition, high log FGF23 (β = -0.43, p = 0.01) and low log Klotho (β = 0.44, p = 0.006) over time were associated with a worse left ventricular diastolic function (cc-TDI e'/a') in CKD-T patients. CONCLUSIONS:In pediatric CKD and CKD-T patients, the FGF23 level increase and Klotho level decrease with progressing renal failure, despite well-controlled phosphate levels. Following adjustments, both high FGF23 and low Klotho levels were strongly associated with a worse left ventricular diastolic function longitudinally. The potential role of FGF23 and Klotho in cardiac morbidity in pediatric CKD requires further investigation.
FGF23 and Left Ventricular Hypertrophy in Children with CKD.
Mitsnefes Mark M,Betoko Aisha,Schneider Michael F,Salusky Isidro B,Wolf Myles Selig,Jüppner Harald,Warady Bradley A,Furth Susan L,Portale Anthony A
Clinical journal of the American Society of Nephrology : CJASN
BACKGROUND AND OBJECTIVES:High plasma concentration of fibroblast growth factor 23 (FGF23) is a risk factor for left ventricular hypertrophy (LVH) in adults with CKD, and induces myocardial hypertrophy in experimental CKD. We hypothesized that high FGF23 levels associate with a higher prevalence of LVH in children with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:We performed echocardiograms and measured plasma C-terminal FGF23 concentrations in 587 children with mild-to-moderate CKD enrolled in the Chronic Kidney Disease in Children (CKiD) study. We used linear and logistic regression to analyze the association of plasma FGF23 with left ventricular mass index (LVMI) and LVH (LVMI ≥95th percentile), adjusted for demographics, body mass index, eGFR, and CKD-specific factors. We also examined the relationship between FGF23 and LVH by eGFR level. RESULTS:Median age was 12 years (interquartile range, 8-15) and eGFR was 50 ml/min per 1.73 m (interquartile range, 38-64). Overall prevalence of LVH was 11%. After adjustment for demographics and body mass index, the odds of having LVH was higher by 2.53 (95% confidence interval, 1.28 to 4.97; <0.01) in participants with FGF23 concentrations ≥170 RU/ml compared with those with FGF23<100 RU/ml, but this association was attenuated after full adjustment. Among participants with eGFR≥45 ml/min per 1.73 m, the prevalence of LVH was 5.4%, 11.2%, and 15.3% for those with FGF23 <100 RU/ml, 100-169 RU/ml, and ≥170 RU/ml, respectively (=0.01). When eGFR was ≥45 ml/min per 1.73 m, higher FGF23 concentrations were independently associated with LVH (fully adjusted odds ratio, 3.08 in the highest versus lowest FGF23 category; 95% confidence interval, 1.02 to 9.24; <0.05; fully adjusted odds ratio, 2.02 per doubling of FGF23; 95% confidence interval, 1.29 to 3.17; <0.01). By contrast, in participants with eGFR<45 ml/min per 1.73 m, FGF23 did not associate with LVH. CONCLUSIONS:Plasma FGF23 concentration ≥170 RU/ml is an independent predictor of LVH in children with eGFR≥45 ml/min per 1.73 m.
Longitudinal FGF23 Trajectories and Mortality in Patients with CKD.
Isakova Tamara,Cai Xuan,Lee Jungwha,Xie Dawei,Wang Xue,Mehta Rupal,Allen Norrina B,Scialla Julia J,Pencina Michael J,Anderson Amanda H,Talierco John,Chen Jing,Fischer Michael J,Steigerwalt Susan P,Leonard Mary B,Hsu Chi-Yuan,de Boer Ian H,Kusek John W,Feldman Harold I,Wolf Myles,
Journal of the American Society of Nephrology : JASN
Elevated fibroblast growth factor 23 (FGF23) levels, measured at a single time, are strongly associated with increased risk of mortality in patients with CKD. There are minimal data on serial FGF23 measurements in CKD. In a prospective case-cohort study of the Chronic Renal Insufficiency Cohort, we measured FGF23 at two to five annual time points (mean 4.0±1.2) in a randomly selected subcohort of 1135 participants, of whom 203 died, and all remaining 390 participants who died through mid-2013. Higher FGF23 was independently associated with increased risk of death in multivariable-adjusted analyses of time-varying FGF23 (hazard ratio per 1-SD increase in ln-transformed FGF23, 1.84; 95% CI, 1.67 to 2.03). Median FGF23 was stable over 5 years of follow-up, but its gradually right-skewed distribution suggested a subpopulation with markedly elevated FGF23. Trajectory analysis revealed three distinct trajectories: stable FGF23 in the majority of participants (slope of lnFGF23 per year =0.03, 95% CI, 0.02 to 0.04, =724) and smaller subpopulations with slowly (slope=0.14, 95% CI, 0.12 to 0.16, =486) or rapidly (slope=0.46, 95% CI, 0.38 to 0.54, =99) rising levels. Compared with stable FGF23, participants with slowly rising FGF23 trajectories were at 4.49-fold higher risk of death (95% CI, 3.17 to 6.35) and individuals with rapidly rising FGF23 trajectories were at 15.23-fold higher risk of death (95% CI, 8.24 to 28.14) in fully adjusted analyses. Trajectory analyses that used four or three annual FGF23 measurements yielded qualitatively similar results. In conclusion, FGF23 levels are stable over time in the majority of patients with CKD, but serial measurements identify subpopulations with rising levels and exceptionally high risk of death.
Effect of ferric citrate hydrate on FGF23 and PTH levels in patients with non-dialysis-dependent chronic kidney disease with normophosphatemia and iron deficiency.
Iguchi Akira,Yamamoto Suguru,Yamazaki Mihoko,Tasaki Kazuyuki,Suzuki Yasushi,Kazama Junichiro James,Narita Ichiei
Clinical and experimental nephrology
BACKGROUND:In patients with normophosphatemia with chronic kidney disease (CKD), fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) increase urinary phosphate excretion while maintaining serum phosphate within the normal range. Recent reports have shown that, in this stage, phosphate binders do not decrease serum FGF23 and PTH levels. Iron deficiency promotes transcription of FGF23 and iron-supplementation for iron deficiency decreases serum FGF23 levels. We hypothesized that ferric citrate hydrate, an iron-based phosphate binder, will decrease serum FGF23 levels in patients with non-dialysis-dependent CKD with normophosphatemia and iron deficiency. METHODS:This was a single-center, randomized, open-label interventional study. The inclusion criteria were as follows: (1) eGFR < 45 mL/min/1.73 m, (2) normophosphatemia, (3) iron deficiency. Patients were assigned to the following groups: ferric citrate hydrate (FCH)-group, sodium ferrous citrate (SFC)-group, and control-group. After 12 weeks of intervention, we evaluated serum FGF23 levels and CKD-mineral bone disorder markers. RESULTS:There were 17 patients in the FCH-group, 14 in the SFC-group, and 9 in the control-group. The serum ferritin levels increased in the FCH-group and SFC-group compared with baseline. Serum FGF23 levels were unchanged; the change in the FCH-group was from 52.91 RU/mL (42.48-72.91) to 40.00 RU/mL (30.30-58.13) (P = 0.1764). However, in the FCH-group, serum PTH levels significantly decreased compared with baseline, from 68.00 pg/mL (49.00-141.00) to 60.00 pg/mL (44.00-144.00) (P = 0.0101). CONCLUSION:Iron-based phosphate binder did not decrease serum FGF23 levels, but decreased serum PTH levels.