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Qiu M, Chang L, Tang G, Ye W, Xu Y, Tulufu N, Dan Z, Qi J, Deng L, Li C. Activation of the osteoblastic HIF-1α pathway partially alleviates the symptoms of STZ-induced type 1 diabetes mellitus via RegIIIγ. Exp Mol Med 2024; 56:1574-1590. [PMID: 38945950 PMCID: PMC11297314 DOI: 10.1038/s12276-024-01257-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 02/04/2024] [Accepted: 03/19/2024] [Indexed: 07/02/2024] Open
Abstract
The hypoxia-inducible factor-1α (HIF-1α) pathway coordinates skeletal bone homeostasis and endocrine functions. Activation of the HIF-1α pathway increases glucose uptake by osteoblasts, which reduces blood glucose levels. However, it is unclear whether activating the HIF-1α pathway in osteoblasts can help normalize glucose metabolism under diabetic conditions through its endocrine function. In addition to increasing bone mass and reducing blood glucose levels, activating the HIF-1α pathway by specifically knocking out Von Hippel‒Lindau (Vhl) in osteoblasts partially alleviated the symptoms of streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM), including increased glucose clearance in the diabetic state, protection of pancreatic β cell from STZ-induced apoptosis, promotion of pancreatic β cell proliferation, and stimulation of insulin secretion. Further screening of bone-derived factors revealed that islet regeneration-derived protein III gamma (RegIIIγ) is an osteoblast-derived hypoxia-sensing factor critical for protection against STZ-induced T1DM. In addition, we found that iminodiacetic acid deferoxamine (SF-DFO), a compound that mimics hypoxia and targets bone tissue, can alleviate symptoms of STZ-induced T1DM by activating the HIF-1α-RegIIIγ pathway in the skeleton. These data suggest that the osteoblastic HIF-1α-RegIIIγ pathway is a potential target for treating T1DM.
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Affiliation(s)
- Minglong Qiu
- Department of Orthopedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China
| | - Leilei Chang
- Department of Orthopedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China
| | - Guoqing Tang
- Kunshan Hospital of Traditional Chinese Medicine, Affiliated Hospital of Yangzhou University, 388 Zuchongzhi Road, Kunshan, 215300, Jiangsu, China
| | - Wenkai Ye
- Department of Orthopedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China
| | - Yiming Xu
- Department of Orthopedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China
| | - Nijiati Tulufu
- Department of Orthopedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China
| | - Zhou Dan
- Department of Orthopedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China
| | - Jin Qi
- Department of Orthopedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China.
| | - Lianfu Deng
- Department of Orthopedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China.
| | - Changwei Li
- Department of Orthopedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China.
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Huang HJ, Hsu BG, Wang CH, Tsai JP, Chen YH, Hung SC, Lin YL. Diabetes mellitus modifies the association between chronic kidney disease-mineral and bone disorder biomarkers and aortic stiffness in peritoneal dialysis patients. Sci Rep 2024; 14:4554. [PMID: 38402283 PMCID: PMC10894213 DOI: 10.1038/s41598-024-55364-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 02/22/2024] [Indexed: 02/26/2024] Open
Abstract
This study aimed to investigate the relationship of four chronic kidney disease-mineral and bone disorder (CKD-MBD) biomarkers, including intact parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), soluble klotho, and fetuin-A, with aortic stiffness in peritoneal dialysis (PD) patients, comparing those with and without diabetes mellitus (DM). A total of 213 patients (mean age 58 ± 14 years; 81 (38.0%) patients with DM) were enrolled. Their aortic pulse wave velocity (PWV) was measured using pressure applanation tonometry, while serum intact PTH, FGF23, α-klotho, and fetuin-A levels were measured using enzyme-linked immunosorbent assay. Overall, patients with DM had higher aortic PWV than those without (9.9 ± 1.8 vs. 8.6 ± 1.4 m/s, p < 0.001). Among the four CKD-MBD biomarkers, FGF23 levels were significantly lower in DM group (462 [127-1790] vs. 1237 [251-3120] pg/mL, p = 0.028) and log-FGF23 independently predicted aortic PWV in DM group (β: 0.61, 95% confidence interval: 0.06-1.16, p = 0.029 in DM group; β: 0.10, 95% confidence interval: - 0.24-0.45, p = 0.546 in nonDM group; interaction p = 0.016). In conclusion, the association between FGF23 and aortic PWV was significantly modified by DM status in PD patients.
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Affiliation(s)
- Hsiang-Jung Huang
- Department of Internal Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 97004, Taiwan
| | - Bang-Gee Hsu
- Department of Internal Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 97004, Taiwan
- School of Medicine, Tzu Chi University, Hualien, 97004, Taiwan
- Division of Nephrology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 97004, Taiwan
| | - Chih-Hsien Wang
- Department of Internal Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 97004, Taiwan
- School of Medicine, Tzu Chi University, Hualien, 97004, Taiwan
- Division of Nephrology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 97004, Taiwan
| | - Jen-Pi Tsai
- School of Medicine, Tzu Chi University, Hualien, 97004, Taiwan
- Division of Nephrology, Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, 62247, Taiwan
| | - Yi-Hsin Chen
- School of Medicine, Tzu Chi University, Hualien, 97004, Taiwan
- Division of Nephrology, Department of Internal Medicine, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, 40201, Taiwan
| | - Szu-Chun Hung
- School of Medicine, Tzu Chi University, Hualien, 97004, Taiwan
- Division of Nephrology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei, 23142, Taiwan
| | - Yu-Li Lin
- Department of Internal Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 97004, Taiwan.
- School of Medicine, Tzu Chi University, Hualien, 97004, Taiwan.
- Division of Nephrology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 97004, Taiwan.
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Magagnoli L, Cozzolino M, Galassi A. The open system of FGF-23 at the crossroad between additional P-lowering therapy, anemia and inflammation: how to deal with the intact and the C-terminal assays? Clin Kidney J 2023; 16:1543-1549. [PMID: 37779858 PMCID: PMC10539210 DOI: 10.1093/ckj/sfad144] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Indexed: 10/03/2023] Open
Abstract
Fibroblast growth factor 23 (FGF-23) has been associated with increased cardiovascular risk and poor survival in dialysis patients. It is well established that FGF-23 synthesis is directly induced by positive phosphate (P) balance. On the other hand, P-lowering treatments such as nutritional P restriction, P binders and dialysis are capable of reducing FGF-23 levels. However, there are many uncertainties regarding the possibility of adopting FGF-23 to guide the clinical decision-making process in the context of chronic kidney disease-mineral bone disorder (CKD-MBD). Furthermore, the best assay to adopt for measurement of FGF-23 levels (namely the intact vs the C-terminal one) remains to be determined, especially in conditions capable of altering the synthesis as well as the cleavage of the intact and biologically active molecule, as occurs in the presence of CKD and its complications. This Editorial discusses the main insights provided by the post hoc analysis of the NOPHOS trial, with particular attention given to evidence-based peculiarities of the intact and the C-terminal assays available for measuring FGF-23 levels, especially in patients receiving additive P-lowering therapy in the presence of inflammation, anemia and iron deficiency.
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Affiliation(s)
- Lorenza Magagnoli
- University of Milan, Department of Health Sciences, Milano, Italy
- ASST Santi Paolo e Carlo, Renal Division, Milano, Italy
| | - Mario Cozzolino
- University of Milan, Department of Health Sciences, Milano, Italy
- ASST Santi Paolo e Carlo, Renal Division, Milano, Italy
| | - Andrea Galassi
- University of Milan, Department of Health Sciences, Milano, Italy
- ASST Santi Paolo e Carlo, Renal Division, Milano, Italy
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Zhang Y, Ran L, Liang Y, Zhang Y, An Z. Safety analysis of pemigatinib leveraging the US Food and Drug administration adverse event reporting system. Front Pharmacol 2023; 14:1194545. [PMID: 37554985 PMCID: PMC10405447 DOI: 10.3389/fphar.2023.1194545] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 07/10/2023] [Indexed: 08/10/2023] Open
Abstract
Background: Cholangiocarcinoma (CCA) is a highly lethal and aggressive epithelial tumor of the hepatobiliary system. A poor prognosis, propensity for relapse, low chance of cure and survival are some of its hallmarks. Pemigatinib, the first targeted treatment for CCA in the United States, has been demonstrated to have a significant response rate and encouraging survival data in early-phase trials. The adverse events (AEs) of pemigatinib must also be determined. Objective: To understand more deeply the safety of pemigatinib in the real world through data-mining of the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Methods: Disproportionality analysis was employed in a retrospective pharmacovigilance investigation to identify the AEs linked to pemigatinib use as signals. Data were collected between 1 January 2020 to 30 June 2022. Four data-mining methods (proportional reporting odds ratio; proportional reporting ratio; Bayesian confidence propagation neural networks of information components; empirical Bayes geometric means) were used to calculate disproportionality. Results: A total of 203 cases using pemigatinib as the prime-suspect medication were found in our search, which involved 99 preferred terms (PTs). Thirteen signals of pemigatinib-induced AEs in seven System Organ Classes were detected after confirming the four algorithms simultaneously. Nephrolithiasis was an unexpected significant AE not listed on the drug label found in our data-mining. Comparison of the differences between pemigatinib and platinum drugs in terms of 33 PTs revealed that 13 PTs also met the criteria of the four algorithms. Ten of these PTs were identical to those compared with all other drugs, in which (excluding a reduction in phosphorus in blood) other PT signal values were higher than those of all other drugs tested. However, comparison of the differences between pemigatinib and infigratinib in terms of the 33 PTs revealed no significant signals in each algorithm method. Conclusion: Some significant signals were detected between pemigatinib use and AEs. PTs with apparently strong signals and PTs not mentioned in the label should be taken seriously.
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Affiliation(s)
| | | | | | | | - Zhuoling An
- Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
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Arboleya L, Braña I, Pardo E, Loredo M, Queiro R. Osteomalacia in Adults: A Practical Insight for Clinicians. J Clin Med 2023; 12:jcm12072714. [PMID: 37048797 PMCID: PMC10094844 DOI: 10.3390/jcm12072714] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 03/26/2023] [Accepted: 04/01/2023] [Indexed: 04/14/2023] Open
Abstract
The term osteomalacia (OM) refers to a series of processes characterized by altered mineralization of the skeleton, which can be caused by various disorders of mineral metabolism. OM can be genetically determined or occur due to acquired disorders, among which the nutritional origin is particularly relevant, due to its wide epidemiological extension and its nature as a preventable disease. Among the hereditary diseases associated with OM, the most relevant is X-linked hypophosphatemia (XLH), which manifests in childhood, although its consequences persist into adulthood where it can acquire specific clinical characteristics, and, although rare, there are XLH cases that reach the third or fourth decade of life without a diagnosis. Some forms of OM present very subtle initial manifestations which cause both considerable diagnosis and treatment delay. On occasions, the presence of osteopenia and fragility fractures leads to an erroneous diagnosis of osteoporosis, which may imply the prescription of antiresorptive drugs (i.e., bisphosphonates or denosumab) with catastrophic consequences for OM bone. On the other hand, some radiological features of OM can be confused with those of axial spondyloarthritis and lead to erroneous diagnoses. The current prevalence of OM is not known and is very likely that its incidence is much higher than previously thought. Moreover, OM explains part of the therapeutic failures that occur in patients diagnosed with other bone diseases. Therefore, it is essential that clinicians who treat adult skeletal diseases take into account the considerations provided in this practical review when focusing on the diagnosis and treatment of their patients with bone diseases.
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Affiliation(s)
- Luis Arboleya
- Rheumatology Division, Hospital Universitario Central de Asturias (HUCA), 33011 Oviedo, Spain
| | - Ignacio Braña
- Rheumatology Division, Hospital Universitario Central de Asturias (HUCA), 33011 Oviedo, Spain
| | - Estefanía Pardo
- Rheumatology Division, Hospital Universitario Central de Asturias (HUCA), 33011 Oviedo, Spain
| | - Marta Loredo
- Rheumatology Division, Hospital Universitario Central de Asturias (HUCA), 33011 Oviedo, Spain
| | - Rubén Queiro
- Rheumatology Division, Hospital Universitario Central de Asturias (HUCA), 33011 Oviedo, Spain
- ISPA Translational Immunology Division, Biohealth Research Institute of the Principality of Asturias (ISPA), 33011 Oviedo, Spain
- School of Medicine, Oviedo University, 33011 Oviedo, Spain
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Marini F, Giusti F, Marasco E, Xumerle L, Kwiatkowska KM, Garagnani P, Biver E, Ferrari S, Iolascon G, Iantomasi T, Brandi ML. High frequency of heterozygous rare variants of the SLC34A1 and SLC9A3R1 genes in patients with atypical femur fracture. Eur J Endocrinol 2023; 188:6986589. [PMID: 36762943 DOI: 10.1093/ejendo/lvad001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 12/12/2022] [Accepted: 01/11/2023] [Indexed: 01/15/2023]
Abstract
OBJECTIVE Atypical femur fractures (AFFs) are rare fragility fractures originating at the lateral cortex of the femur, affecting the subtrochanteric or diaphyseal area of thebone with a transverse morphology. Occurrence of AFF is specifically associated with a small number of rare monogenic congenital metabolic bone disorders, such as hypophosphatasia, and with long-term treatment with antiresorptiondrugs. The exact pathogenesis of these fractures remains poorly understood and, except for cases of diagnosed HPP or other AFF-causing bone diseases, it is not possible to assess which patients are at higher riskof developing AFFs as a consequence of anti-resorption therapy. DESIGN We genetically screened 25 unrelated patients who had developed at least one AFF. INTERVENTION Genetic screening was performed through a nextgeneration sequencing analysis with a customized panel containing 76 human genes involved in the regulation of the mineralization processWe genetically screened 25 unrelated patients who had developed at least one AFF. RESULTS We found a relatively high frequency (32.0%) of heterozygous rare variants inthe SLC34A1 and SLC9A3R1 genes, two genes whose heterozygous inactivating mutations have been respectively associated with autosomal dominant hypophosphatemic nephrolithiasis/osteoporosis types 1 and 2 (NPHLOP1and NPHLOP2). Other heterozygous rare variants were found in the BMPR1B, CYP27B1, FBN1, MEPE, PIGO, and PHOSPHO1 genes, each in a single AFF case (4.0%). CONCLUSIONS AND RELEVANCE Our findings suggest that rarevariants of SLC34A1 and SLC9A3R1 could represent a possible genetic risk factor for the occurrence of AFFs. On the other hand, AFFs could represent an unsuspected clinical manifestation and/or an anti-resorption therapycorrelatedadverse event in patients with NPHLOP disorders.
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Affiliation(s)
- Francesca Marini
- FirmoLab, FIRMO Onlus, Italian Foundation for the Research on Bone Diseases, Florence 50141, Italy
| | - Francesca Giusti
- Donatello Bone Clinic, Villa Donatello Hospital, Sesto Fiorentino 50019, Italy
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50139, Italy
| | - Elena Marasco
- Laboratory of Human Genetics, Personal Genomics SRL, Verona 37136, Italy
| | - Luciano Xumerle
- Laboratory of Human Genetics, Personal Genomics SRL, Verona 37136, Italy
| | | | - Paolo Garagnani
- Laboratory of Human Genetics, Personal Genomics SRL, Verona 37136, Italy
- Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), University of Bologna, Bologna 40126, Italy
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
| | - Emmanuel Biver
- Division of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland
| | - Serge Ferrari
- Division of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland
| | - Giovanni Iolascon
- Department of Medical and Surgical Specialties and Dentistry, University of Campania "Luigi Vanvitelli", Naples 80138, Italy
| | - Teresa Iantomasi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50139, Italy
| | - Maria Luisa Brandi
- FirmoLab, FIRMO Onlus, Italian Foundation for the Research on Bone Diseases, Florence 50141, Italy
- Donatello Bone Clinic, Villa Donatello Hospital, Sesto Fiorentino 50019, Italy
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Corradi V, Samoni S, Mariotto A, Caprara C, Scalzotto E, Frigo AC, Martino FK, Giavarina D, Ronco C, Zanella M. Relationship between Residual Urine Output and Type of Dialysis with FGF23 Levels. J Clin Med 2022; 12:jcm12010222. [PMID: 36615023 PMCID: PMC9821742 DOI: 10.3390/jcm12010222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 12/13/2022] [Accepted: 12/21/2022] [Indexed: 12/30/2022] Open
Abstract
Several studies investigated the role of fibroblast growth factor 23 (FGF23) in the regulation of renal phosphate excretion in chronic kidney disease (CKD). However, patients with residual urine output (UO) seem to control their serum phosphorus levels better. Our aim was to determine whether FGF23 levels are influenced by dialysis modality and UO. We performed a cross-sectional study in hemodialysis (HD) and peritoneal dialysis (PD) patients. The C-terminal FGF23 (cFGF23) levels were determined in plasma with a two-site enzyme-linked immunosorbent assay. The UO collection referred to an mL/day measurement. All p values were two-sided, and the statistical significance was set at p < 0.05. We enrolled 133 patients (58 HD, 75 PD, UO 70%). The median cFGF23 was significantly higher in HD vs. PD patients (p = 0.0017) and not significantly higher in patients without UO (p = 0.12). We found a negative correlation between cFGF23 and the UO volume (p = 0.0250), but the correlation was not significant when considering the type of dialysis treatment. Phosphorus (ß = 0.21677; p = 0.0007), type of dialysis (ß = −0.68392; p = 0.0003), and creatinine (ß = 0.08130; p = 0.0133) were significant and independent predictors of cFGF23 levels. In conclusion, cFGF23 was significantly higher in HD than in PD patients. We found a significant negative correlation between cFGF23 and the residual UO volume, but the correlation was not significant considering the type of dialysis. Our study reveals that dialysis modality is an independent predictor of FGF23 levels. In particular, PD is associated with lower FGF23 levels than HD.
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Affiliation(s)
- Valentina Corradi
- Department of Nephrology, Dialysis and Transplantation, San Bortolo Hospital, AULSS 8 BERICA Vicenza, 36100 Vicenza, Italy
- International Renal Research Institute of Vicenza and IRRIV Foundation for Research, San Bortolo Hospital, AULSS 8 BERICA Vicenza, 36100 Vicenza, Italy
- Correspondence: ; Tel.: +39-0444-753650
| | - Sara Samoni
- International Renal Research Institute of Vicenza and IRRIV Foundation for Research, San Bortolo Hospital, AULSS 8 BERICA Vicenza, 36100 Vicenza, Italy
- Department of Nephrology and Dialysis, S. Anna Hospital, ASST Lariana, 22077 Como, Italy
| | - Alice Mariotto
- Department of Nephrology, Dialysis and Transplantation, San Bortolo Hospital, AULSS 8 BERICA Vicenza, 36100 Vicenza, Italy
- International Renal Research Institute of Vicenza and IRRIV Foundation for Research, San Bortolo Hospital, AULSS 8 BERICA Vicenza, 36100 Vicenza, Italy
| | - Carlotta Caprara
- Department of Nephrology, Dialysis and Transplantation, San Bortolo Hospital, AULSS 8 BERICA Vicenza, 36100 Vicenza, Italy
- International Renal Research Institute of Vicenza and IRRIV Foundation for Research, San Bortolo Hospital, AULSS 8 BERICA Vicenza, 36100 Vicenza, Italy
| | - Elisa Scalzotto
- International Renal Research Institute of Vicenza and IRRIV Foundation for Research, San Bortolo Hospital, AULSS 8 BERICA Vicenza, 36100 Vicenza, Italy
| | - Anna Chiara Frigo
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35122 Padua, Italy
| | - Francesca K. Martino
- Department of Nephrology, Dialysis and Transplantation, San Bortolo Hospital, AULSS 8 BERICA Vicenza, 36100 Vicenza, Italy
- International Renal Research Institute of Vicenza and IRRIV Foundation for Research, San Bortolo Hospital, AULSS 8 BERICA Vicenza, 36100 Vicenza, Italy
| | - Davide Giavarina
- Department of Laboratory Medicine, San Bortolo Hospital, AULSS 8 BERICA Vicenza, 36100 Vicenza, Italy
| | - Claudio Ronco
- International Renal Research Institute of Vicenza and IRRIV Foundation for Research, San Bortolo Hospital, AULSS 8 BERICA Vicenza, 36100 Vicenza, Italy
- University of Padova, 35122 Padua, Italy
| | - Monica Zanella
- Department of Nephrology, Dialysis and Transplantation, San Bortolo Hospital, AULSS 8 BERICA Vicenza, 36100 Vicenza, Italy
- International Renal Research Institute of Vicenza and IRRIV Foundation for Research, San Bortolo Hospital, AULSS 8 BERICA Vicenza, 36100 Vicenza, Italy
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Miyakawa H, Hsu HH, Ogawa M, Akabane R, Miyagawa Y, Takemura N. Association between serum fibroblast growth factor-23 concentrations and blood calcium levels in chronic kidney disease cats with upper urolithiasis. J Feline Med Surg 2022; 24:1245-1252. [PMID: 35133180 PMCID: PMC10812369 DOI: 10.1177/1098612x221075278] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVES This study investigated whether serum fibroblast growth factor (FGF)-23 concentrations are associated with serum total calcium (tCa) and blood ionised calcium (iCa) concentrations in cats with chronic kidney disease (CKD) and upper urolithiasis. METHODS Serum samples and the medical records of cats with CKD with nephroliths, ureteroliths or both were investigated retrospectively. Cats with a serum creatinine concentration >250 μmol/l and/or a serum phosphorus concentration ⩾1.50 mmol/l were excluded. Based on cut-offs for serum tCa (2.70 mmol/l) or blood iCa (1.40 mmol/l), cats were divided into the following groups: total hypercalcaemia (H-tCa) (>2.70 mmol/l) and total normocalcaemia (N-tCa) (⩽2.70 mmol/l) groups, or ionised hypercalcaemia (H-iCa) (>1.40 mmol/l) and ionised normocalcaemia (N-iCa) (⩽1.40 mmol/l) groups, respectively. Serum FGF-23 concentrations were compared between groups and correlation analysis was performed. RESULTS Thirty-two cats with CKD and upper urolithiasis were included. Serum FGF-23 concentrations in the H-tCa group (median 573 pg/ml [range 125-3888]; n = 12) were significantly higher compared with the N-tCa group (median 245 pg/ml [range 94-627]; n = 20) (P = 0.001). Serum FGF-23 concentrations in the H-iCa group (median 1479 pg/ml [range 509-3888]; n = 6) increased significantly compared with the N-iCa group (median 245 pg/ml [range 94-637]; n = 26) (P <0.001). Serum FGF-23 concentrations significantly correlated with serum tCa (r = 0.511, P = 0.003) and blood iCa concentrations (r = 0.425, P = 0.015) but not serum creatinine (r = 0.279, P = 0.122) or phosphorus concentrations (r = 0.208, P = 0.253).Conclusions and relevance Increased serum FGF-23 concentrations were associated with hypercalcaemia independently of creatinine and phosphate status in cats with CKD and upper urolithiasis.
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Affiliation(s)
- Hirosumi Miyakawa
- Laboratory of Veterinary Internal Medicine II, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan
| | - Huai-Hsun Hsu
- Laboratory of Veterinary Internal Medicine II, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan
| | - Mizuki Ogawa
- Laboratory of Veterinary Internal Medicine II, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan
| | - Ryota Akabane
- Laboratory of Veterinary Internal Medicine II, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan
| | - Yuichi Miyagawa
- Laboratory of Veterinary Internal Medicine II, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan
| | - Naoyuki Takemura
- Laboratory of Veterinary Internal Medicine II, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan
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Multiple nutrient transporters enable cells to mitigate a rate-affinity tradeoff. PLoS Comput Biol 2022; 18:e1010060. [PMID: 35468136 PMCID: PMC9071158 DOI: 10.1371/journal.pcbi.1010060] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 05/05/2022] [Accepted: 03/26/2022] [Indexed: 01/07/2023] Open
Abstract
Eukaryotic genomes often encode multiple transporters for the same nutrient. For example, budding yeast has 17 hexose transporters (HXTs), all of which potentially transport glucose. Using mathematical modelling, we show that transporters that use either facilitated diffusion or symport can have a rate-affinity tradeoff, where an increase in the maximal rate of transport decreases the transporter’s apparent affinity. These changes affect the import flux non-monotonically, and for a given concentration of extracellular nutrient there is one transporter, characterised by its affinity, that has a higher import flux than any other. Through encoding multiple transporters, cells can therefore mitigate the tradeoff by expressing those transporters with higher affinities in lower concentrations of nutrients. We verify our predictions using fluorescent tagging of seven HXT genes in budding yeast and follow their expression over time in batch culture. Using the known affinities of the corresponding transporters, we show that their regulation in glucose is broadly consistent with a rate-affinity tradeoff: as glucose falls, the levels of the different transporters peak in an order that mostly follows their affinity for glucose. More generally, evolution is constrained by tradeoffs. Our findings indicate that one such tradeoff often occurs in the cellular transport of nutrients. From yeast to humans, cells often express multiple different types of transporters for the same nutrient, and it is puzzling why a single high-affinity transporter is not expressed instead. Here we initially use mathematical modelling to demonstrate that transporters facilitating diffusion and those powered by the proton motive force can both exhibit a rate-affinity tradeoff, for quite general conditions. A transporter with a higher affinity necessarily has a lower rate, and vice versa. The tradeoff implies that there is a range of nutrient concentrations for which a transporter, characterised by its affinity, has a higher import flux than any other transporter with a different affinity. To mitigate the tradeoff, genomes may therefore encode multiple different transporters, and cells that express each transporter in the concentrations where it imports best will uptake nutrients at higher rates. Consistently, we show that as cells of budding yeast consume glucose, they express five types of hexose transporters in an order that follows the transporters’ affinities.
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10
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How the diagnosis and the management of genetic renal phosphate leak impact the life of kidney stone formers? Urolithiasis 2022; 50:319-331. [DOI: 10.1007/s00240-022-01316-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 02/08/2022] [Indexed: 10/19/2022]
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11
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Grapin M, Gaillard F, Biebuyck N, Ould-Rabah M, Hennequin C, Berthaud R, Dorval G, Blanc T, Hourmant M, Kamar N, Rostaing L, Couzi L, Garcelon N, Prié D, Boyer O, Bienaimé F. The spectrum of kidney function alterations in adolescents with a solitary functioning kidney. Pediatr Nephrol 2021; 36:3159-3168. [PMID: 33895898 DOI: 10.1007/s00467-021-05074-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 03/10/2021] [Accepted: 03/25/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND A precise assessment of glomerular filtration rate is key to delineate the care of children with a solitary functioning kidney (SFK). Data regarding measured GFR (mGFR) in this population is restricted to a single study of 77 individuals, which suggested that a GFR estimation (eGFR) method based on creatinine and cystatin C (eGFR-CKiD2) performed better than Schwartz's equation (eGFR-Schwartz). METHODS We measured GFR in 210 consecutive adolescents (7 to 22 years old) with an SFK referred to our institution between 2014 and 2019 and in 43 young candidates for kidney donation (18 to 25 years old). We compared the distribution of mGFR in both groups and determined the factors associated with reduced mGFR in adolescents with an SFK. We further compared different eGFR formulas with mGFR and assessed the association of mGFR and eGFRs with PTH and FGF23, two early indicators of GFR reduction. RESULTS While adolescents with an SFK had a similar median mGFR to healthy controls (103 ± 24ml/min/1.73m2 vs. 107 ± 12 ml/min/1.73m2), the fraction of individuals with an mGFR below 90 ml/min/1.73m2 was higher in patients with SFK (23% vs. 5% in controls; P = 0.005). Multiple linear regression identified older age, ipsilateral abnormalities of the urinary tract, lack of compensatory hypertrophy, and treated hypertension as independent factors associated with reduced mGFR. A smaller bias using eGFR-Schwartz (95% confidence interval (95%CI): 3 to 7) was revealed when compared to other eGFR. Compared to eGFR-Schwartz, mGFR showed a stronger correlation with PTH (r = 0.04 vs. r = 0.1) and FGF23 (r = 0.03 vs. r = 0.05). CONCLUSION SFK is not a benign condition, since 20% of the patients display altered kidney function. Our results raise caution regarding the use of the cystatin-based equation. mGFR shows a better ability than eGFR-Schwartz to differentiate patients showing early homeostatic adaptation to GFR reduction.
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Affiliation(s)
- Mathilde Grapin
- Service de Néphrologie Pédiatrique, Centre de référence Marhea, Hôpital Necker-Enfants malades, Assistance Publique-Hôpitaux de Paris, Paris, France
- Université de Paris, Institut Necker-Enfants Malades Inserm U1151, Paris, France
- Sorbonne Université, Paris, France
| | - François Gaillard
- Service de Néphrologie, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Nathalie Biebuyck
- Service de Néphrologie Pédiatrique, Centre de référence Marhea, Hôpital Necker-Enfants malades, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Melissa Ould-Rabah
- Service de Physiologie, Hôpital Necker-Enfants malades, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Carole Hennequin
- Service de Biochimie, Hôpital Necker-Enfants malades, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Romain Berthaud
- Service de Néphrologie Pédiatrique, Centre de référence Marhea, Hôpital Necker-Enfants malades, Assistance Publique-Hôpitaux de Paris, Paris, France
- Institut Imagine, Inserm U1163, Université de Paris, Paris, France
| | - Guillaume Dorval
- Service de Néphrologie Pédiatrique, Centre de référence Marhea, Hôpital Necker-Enfants malades, Assistance Publique-Hôpitaux de Paris, Paris, France
- Institut Imagine, Inserm U1163, Université de Paris, Paris, France
| | - Thomas Blanc
- Université de Paris, Institut Necker-Enfants Malades Inserm U1151, Paris, France
- Service de Chirurgie Pédiatrie, Hôpital Necker-Enfants malades, Assistance Publique-Hôpitaux de Paris, Paris, France
| | | | - Nassim Kamar
- Service de Néphrologie et de Transplantation, CHU Rangueil, Toulouse, France
| | - Lionel Rostaing
- Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation, Centre Hospitalier Universitaire Grenoble-Alpes, Grenoble, France
| | - Lionel Couzi
- Service de Néphrologie, Transplantation, Dialyse et Aphérèse, CHU de Bordeaux, Bordeaux, France
| | - Nicolas Garcelon
- Institut Imagine, Inserm U1163, Université de Paris, Paris, France
| | - Dominique Prié
- Université de Paris, Institut Necker-Enfants Malades Inserm U1151, Paris, France
- Service de Physiologie, Hôpital Necker-Enfants malades, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Olivia Boyer
- Service de Néphrologie Pédiatrique, Centre de référence Marhea, Hôpital Necker-Enfants malades, Assistance Publique-Hôpitaux de Paris, Paris, France
- Institut Imagine, Inserm U1163, Université de Paris, Paris, France
| | - Frank Bienaimé
- Université de Paris, Institut Necker-Enfants Malades Inserm U1151, Paris, France.
- Service de Physiologie, Hôpital Necker-Enfants malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
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12
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Miyakawa H, Hsu HH, Ogawa M, Akabane R, Miyagawa Y, Takemura N. Association between serum fibroblast growth factor-23 concentration and development of hyperphosphatemia in normophosphatemic dogs with chronic kidney disease. J Vet Intern Med 2021; 35:2296-2305. [PMID: 34418162 PMCID: PMC8478064 DOI: 10.1111/jvim.16237] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 07/22/2021] [Accepted: 07/22/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Fibroblast growth factor (FGF)-23 is increased first in the sequence of changes associated with chronic kidney disease (CKD)-mineral and bone disorder. Thus, its measurement may serve as a predictive indicator of incident hyperphosphatemia. OBJECTIVES To investigate whether serum FGF-23 concentration in normophosphatemic dogs with CKD is associated with the risk of the subsequent development of hyperphosphatemia and CKD progression. ANIMALS Forty-two normophosphatemic dogs with CKD. METHODS Blood samples and medical records were retrospectively investigated. Hyperphosphatemia was defined as a serum phosphorous concentration >5.0 mg/dL. Progression was defined as a >1.5-fold increase in serum creatinine concentration. The time periods and hazard ratios for these outcomes were assessed using Kaplan-Meier analysis, log-rank test, and univariate Cox regression analysis. The variables associated with the outcomes in the univariate analysis were included in the multivariate Cox regression model with backward selection. RESULTS Serum FGF-23 concentration >528 pg/mL was associated with a shorter time to development of hyperphosphatemia (P < .001) and CKD progression (P < .001). In multiple Cox regression analysis, increased FGF-23 concentration remained a significant variable associated with these outcomes (P < .05). CONCLUSIONS AND CLINICAL IMPORTANCE Increased FGF-23 concentration in normophosphatemic dogs with CKD was associated with significant risk of development of hyperphosphatemia, independent of CKD stage, and of the progression of CKD. Future research focusing on whether interventions that decrease FGF-23 secretion will slow the development of hyperphosphatemia and CKD progression is needed.
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Affiliation(s)
- Hirosumi Miyakawa
- Laboratory of Veterinary Internal Medicine II, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Huai-Hsun Hsu
- Laboratory of Veterinary Internal Medicine II, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Mizuki Ogawa
- Laboratory of Veterinary Internal Medicine II, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Ryota Akabane
- Laboratory of Veterinary Internal Medicine II, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Yuichi Miyagawa
- Laboratory of Veterinary Internal Medicine II, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Naoyuki Takemura
- Laboratory of Veterinary Internal Medicine II, Nippon Veterinary and Life Science University, Tokyo, Japan
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Blumenstein I, Shanbhag S, Langguth P, Kalra PA, Zoller H, Lim W. Newer formulations of intravenous iron: a review of their chemistry and key safety aspects - hypersensitivity, hypophosphatemia, and cardiovascular safety. Expert Opin Drug Saf 2021; 20:757-769. [PMID: 33993818 DOI: 10.1080/14740338.2021.1912010] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Introduction: The newest intravenous (IV) iron products show an improved safety profile over predecessors, allowing for the rapid administration of relatively high doses. Ferric derisomaltose (FDI; also known as iron isomaltoside), ferric carboxymaltose (FCM), and ferumoxytol (FER), are successful treatments for iron deficiency (Europe; FDI and FCM) and iron deficiency anemia (US; FDI, FCM, and FER).Areas covered: This review focusses on the chemistry and structure of FDI, FCM, and FER, and on three key aspects of IV iron safety: (1) hypersensitivity; (2) hypophosphatemia and sequelae; (3) cardiovascular safety.Expert opinion: Although the safety of modern IV iron has improved, immediate infusion reactions and the development of hypophosphatemia must be appreciated and recognized by those who prescribe and administer IV iron. Immediate infusion reactions can occur with any IV iron and are usually mild; severe reactions - particularly anaphylaxis - are extremely rare. The recognition and appropriate management of infusion reactions is an important consideration to the successful administration of IV iron. Severe, persistent, hypophosphatemia is a specific side effect of FCM. No cardiovascular safety signal has been identified for IV iron. Ongoing trials in heart failure will provide additional long-term efficacy and safety data.
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Affiliation(s)
- Irina Blumenstein
- Medical Department 1, Department of Gastroenterology, Hepatology, and Clinical Nutrition, University Clinic Frankfurt, Frankfurt, Germany
| | - Satish Shanbhag
- Department of Hematology/Medical Oncology, Cancer Specialists of North Florida, Fleming Island, FL, USA.,Division of Hematology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MA, USA
| | - Peter Langguth
- Institute of Pharmacy and Biochemistry, Department of Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University, Mainz, Germany
| | - Philip A Kalra
- Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford, UK.,Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Heinz Zoller
- Department of Medicine I, Gastroenterology, Hepatology and Endocrinology, Medical University of Innsbruck, Innsbruck, Austria
| | - Wendy Lim
- Department of Medicine, Division of Hematology and Thromboembolism, St. Joseph's Healthcare Hamilton, McMaster University, Hamilton, ON, Canada
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Pimentel A, Ureña-Torres P, Bover J, Luis Fernandez-Martín J, Cohen-Solal M. Bone Fragility Fractures in CKD Patients. Calcif Tissue Int 2021; 108:539-550. [PMID: 33219822 PMCID: PMC8052229 DOI: 10.1007/s00223-020-00779-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 11/04/2020] [Indexed: 12/14/2022]
Abstract
Chronic kidney diseases (CKD) are associated with mineral and bone diseases (MBD), including pain, bone loss, and fractures. Bone fragility related to CKD includes the risk factors observed in osteoporosis in addition to those related to CKD, resulting in a higher risk of mortality related to fractures. Unawareness of such complications led to a poor management of fractures and a lack of preventive approaches. The current guidelines of the Kidney Disease Improving Global Outcomes (KDIGO) recommend the assessment of bone mineral density if results will impact treatment decision. In addition to bone density, circulating biomarkers of mineral, serum bone turnover markers, and imaging techniques are currently available to evaluate the fracture risk. The purpose of this review is to provide an overview of the epidemiology and pathogenesis of CKD-associated bone loss. The contribution of the current tools and other techniques in development are discussed. We here propose a current view of how to better predict bone fragility and the therapeutic options in CKD.
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Affiliation(s)
| | - Pablo Ureña-Torres
- AURA Paris-Nord, Saint-Ouen, France
- Necker Hospital, University of Paris Descartes, Department of Renal Physiology, Paris, France
| | - Jordi Bover
- Fundació Puigvert, Universitat Autònoma, IIB Sant Pau, REDinREN, Nephrology Department, Barcelona, Catalonia, Spain
| | - Jose Luis Fernandez-Martín
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), REDinREN del ISCIII, Hospital Universitario Central de Asturias. Universidad de Oviedo, Bone and Mineral Research Unit, Oviedo, Asturias, Spain
| | - Martine Cohen-Solal
- INSERM U1132 & Université de Paris, Hôpital Lariboisière, Department of Rheumatology, Paris, France.
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15
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Molin A, Lemoine S, Kaufmann M, Breton P, Nowoczyn M, Ballandonne C, Coudray N, Mittre H, Richard N, Ryckwaert A, Lavillaureix A, Jones G, Bacchetta J, Kottler ML. Overlapping Phenotypes Associated With CYP24A1, SLC34A1, and SLC34A3 Mutations: A Cohort Study of Patients With Hypersensitivity to Vitamin D. Front Endocrinol (Lausanne) 2021; 12:736240. [PMID: 34721296 PMCID: PMC8548709 DOI: 10.3389/fendo.2021.736240] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Accepted: 09/07/2021] [Indexed: 12/14/2022] Open
Abstract
Mutations in CYP24A1 (vitamin D 24-hydroxylase) and SLC34A1 (renal phosphate transporter NPT2a) cause autosomal recessive Infantile Hypercalcemia type 1 and 2, illustrating links between vitamin D and phosphate metabolism. Patients may present with hypercalciuria and alternate between chronic phases with normal serum calcium but inappropriately high 1,25-(OH)2D and appropriately low PTH, and acute phases with hypercalcemia with suppressed PTH. Mutations in SLC34A3 and SLC9A3R1 have been associated with phosphate wasting without hypercalcemia. The aims of this study were to evaluate the frequency of mutations in these genes in patients with a medical history suggestive of CYP24A1 mutation to search for a specific pattern. Using next generation sequencing, we screened for mutations in 185 patients with PTH levels < 20 pg/mL, hypercalcemia and/or hypercalciuria, and relatives. Twenty-eight (15%) patients harbored biallelic mutations in CYP24A1 (25) and SLC34A3 (3), mostly associated with renal disease (lithiasis, nephrocalcinosis) (86%). Hypophosphatemia was found in 7 patients with biallelic mutations in CYP24A1 and a normal phosphatemia was reported in 2 patients with biallelic mutations in SLC34A3. Rare variations in SLC34A1 and SLC34A3 were mostly of uncertain significance. Fifteen patients (8%) carried only one heterozygous mutation. Heterozygous relatives carrying SLC34A1 or SLC34A3 variation may present with biochemical changes in mineral metabolism. Two patients' genotype may suggest digenism (heterozygous variations in different genes). No variation was found in SLC9A3R1. As no specific pattern can be found, patients with medical history suggestive of CYP24A1 mutation should benefit from SLC34A1 and SLC34A3 analysis.
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Affiliation(s)
- Arnaud Molin
- Caen University Hospital, Department of Genetics, Molecular Genetics Laboratory and Reference Center for Rare Diseases of Calcium and Phosphorus Metabolism (OSCAR), Caen, France
- Caen Normandy University, Medical School, Caen, France
- BioTARGEN, Caen Normandy University, Caen, France
- OeReCa, Caen Normandy University, Caen, France
- *Correspondence: Arnaud Molin,
| | - Sandrine Lemoine
- Department of Nephrology and Renal Functional Explorations, Edouard Herriot Hospital, Lyon, France
- University of Lyon, University of Lyon 1, Villeurbanne, France
| | - Martin Kaufmann
- Queen’s University, Department of Biomedical and Molecular Sciences, Kingston, ON, Canada
| | - Pierre Breton
- Caen University Hospital, Department of Genetics, Molecular Genetics Laboratory and Reference Center for Rare Diseases of Calcium and Phosphorus Metabolism (OSCAR), Caen, France
| | - Marie Nowoczyn
- Caen Normandy University, Medical School, Caen, France
- Caen University Hospital, Department of Biochemistry, Caen, France
| | | | - Nadia Coudray
- Caen University Hospital, Department of Genetics, Molecular Genetics Laboratory and Reference Center for Rare Diseases of Calcium and Phosphorus Metabolism (OSCAR), Caen, France
| | - Hervé Mittre
- Caen University Hospital, Department of Genetics, Molecular Genetics Laboratory and Reference Center for Rare Diseases of Calcium and Phosphorus Metabolism (OSCAR), Caen, France
- Caen Normandy University, Medical School, Caen, France
- OeReCa, Caen Normandy University, Caen, France
| | - Nicolas Richard
- Caen University Hospital, Department of Genetics, Molecular Genetics Laboratory and Reference Center for Rare Diseases of Calcium and Phosphorus Metabolism (OSCAR), Caen, France
- BioTARGEN, Caen Normandy University, Caen, France
| | - Amélie Ryckwaert
- Department of Pediatrics, Rennes University Hospital, Rennes, France
| | | | - Glenville Jones
- Queen’s University, Department of Biomedical and Molecular Sciences, Kingston, ON, Canada
| | - Justine Bacchetta
- University of Lyon, University of Lyon 1, Villeurbanne, France
- Reference Center for Rare Kidney Diseases (ORKID), Department of Pediatric Nephrology, Rhumatology and Dermatology, Woman Mother Children Hospital, Bron, France
- Reference Center for Rare Diseases of Calcium and Phosphorus Metabolism (OSCAR), Department of Pediatric Nephrology, Rhumatology and Dermatology, Woman Mother Children Hospital, Bron, France
- INSERM 1033, Bone Diseases Prevention, Lyon, France
| | - Marie-Laure Kottler
- Caen University Hospital, Department of Genetics, Molecular Genetics Laboratory and Reference Center for Rare Diseases of Calcium and Phosphorus Metabolism (OSCAR), Caen, France
- Caen Normandy University, Medical School, Caen, France
- BioTARGEN, Caen Normandy University, Caen, France
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Jiang J, Li Y, Zheng D, Wang Z, Zhou H, Liu G. Fortified phosphorus‑lowering treatment through administration of lanthanum protects against vascular calcification via regulation of FGF23 in chronic kidney disease. Int J Mol Med 2020; 46:1783-1793. [PMID: 32901861 PMCID: PMC7521475 DOI: 10.3892/ijmm.2020.4719] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 03/06/2020] [Indexed: 12/15/2022] Open
Abstract
Phosphorus reduction can prevent against vascular calcification (VC) in chronic kidney disease (CKD), but the mechanisms underlying its actions remain unclear. The aim of the present study was to determine the effect of a fortified phosphorus-lowing treatment on VC in CKD. Serum levels of creatinine, blood urea nitrogen (BUN), fibroblast growth factor 23 (FGF23), calcium and phosphorus, and the plasma levels of parathyroid hormone (PTH) were determined in an animal model of CKD treated with or without lanthanum. Haematoxylin and eosin (H&E) staining was performed to examine the structure of kidney tissues. Western blot analysis was performed to compare the levels of total- (t-) extracellular signal-related kinase (ERK) and phospho- (p-)ERK among the different experimental groups to investigate the effect of FGF23 on p-ERK expression. In the animal model, administration of adenine increased the serum levels of creatinine, BUN, FGF23 and phosphorus but decreased the serum levels of calcium. In addition, adenine treatment increased the plasma levels of PTH. H&E staining showed that lanthanum treatment did not alter the severity of renal cortex injury. Furthermore, the levels of t-ERK levels did not notably differ between the Adenine-free, Adenine-vehicle and Adenine-lanthanum groups, whereas the levels of p-ERK and aortic calcium in the Adenine-vehicle group were significantly upregulated. In addition, ectopic overexpression of FGF23 increased the levels of p-ERK, Msx2 and Osx in a dose-dependent manner. Furthermore, a total of 48 patients were enrolled in the present study. In the fortified group, the serum levels of FGF23, phosphorus and PTH were significantly reduced, whereas the serum levels of calcium were significantly increased, indicating an enhanced preventative effect in the fortified group. The results of the present study suggest that FGF23 may be used as a therapeutic target in the management and prevention of VC in CKD.
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Affiliation(s)
- Jie Jiang
- Nephrology Department, Dongguan People's Hospital Affiliated to Southern Medical University, Dongguan, Guangdong 523059, P.R. China
| | - Yi Li
- Nephrology Department, Dongguan People's Hospital Affiliated to Southern Medical University, Dongguan, Guangdong 523059, P.R. China
| | - Dongwen Zheng
- Nephrology Department, Dongguan People's Hospital Affiliated to Southern Medical University, Dongguan, Guangdong 523059, P.R. China
| | - Zhen Wang
- Nephrology Department, Dongguan People's Hospital Affiliated to Southern Medical University, Dongguan, Guangdong 523059, P.R. China
| | - Hongmei Zhou
- Nephrology Department, Dongguan People's Hospital Affiliated to Southern Medical University, Dongguan, Guangdong 523059, P.R. China
| | - Guohui Liu
- Nephrology Department, Dongguan People's Hospital Affiliated to Southern Medical University, Dongguan, Guangdong 523059, P.R. China
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Agoro R, Ni P, Noonan ML, White KE. Osteocytic FGF23 and Its Kidney Function. Front Endocrinol (Lausanne) 2020; 11:592. [PMID: 32982979 PMCID: PMC7485387 DOI: 10.3389/fendo.2020.00592] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 07/20/2020] [Indexed: 12/16/2022] Open
Abstract
Osteocytes, which represent up to 95% of adult skeletal cells, are deeply embedded in bone. These cells exhibit important interactive abilities with other bone cells such as osteoblasts and osteoclasts to control skeletal formation and resorption. Beyond this local role, osteocytes can also influence the function of distant organs due to the presence of their sophisticated lacunocanalicular system, which connects osteocyte dendrites directly to the vasculature. Through these networks, osteocytes sense changes in circulating metabolites and respond by producing endocrine factors to control homeostasis. One critical function of osteocytes is to respond to increased blood phosphate and 1,25(OH)2 vitamin D (1,25D) by producing fibroblast growth factor-23 (FGF23). FGF23 acts on the kidneys through partner fibroblast growth factor receptors (FGFRs) and the co-receptor Klotho to promote phosphaturia via a downregulation of phosphate transporters, as well as the control of vitamin D metabolizing enzymes to reduce blood 1,25D. In the first part of this review, we will explore the signals involved in the positive and negative regulation of FGF23 in osteocytes. In the second portion, we will bridge bone responses with the review of current knowledge on FGF23 endocrine functions in the kidneys.
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Affiliation(s)
- Rafiou Agoro
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Pu Ni
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Megan L. Noonan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Kenneth E. White
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
- Medicine/Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States
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18
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Cohen-Solal M, Funck-Brentano T, Ureña Torres P. Bone fragility in patients with chronic kidney disease. Endocr Connect 2020; 9:R93-R101. [PMID: 32168473 PMCID: PMC7219138 DOI: 10.1530/ec-20-0039] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 03/13/2020] [Indexed: 11/23/2022]
Abstract
Mineral and bone diseases (MBD) are predominant in patients with chronic kidney disease (CKD) and lead to several bone manifestations, from pain to skeletal fractures. Cumulative traditional clinical risk factors, such as age and gender, in addition to those related to CKD, enhance the risk of comorbidity and mortality related to fractures. Despite great advances in understanding MBD in CKD, clinical and biological targets are lacking, which leads to under-management of fractures. Optimal PTH control results in a net improvement in defining the levels of bone remodeling. In addition, circulating biomarkers such as bone-specific alkaline phosphatase and cross-linked collagen type I peptide will also provide additional information about remodeling rate, bone mineralization and the evaluation of fracture risk. Imaging techniques identify patients at risk by measurement of bone mineral density by DEXA or by high peripheral QCT, which allow the discrimination of trabecular and cortical bone. Here, we have reviewed the literature related to epidemiology and the pathophysiological role of mineral and biochemical factors involved in CKD-MBD with a special focus on fracture risk. We also provide an algorithm that could be used for the management of bone diseases and to guide treatment decisions. Finally, the combined expertise of clinicians from various disciplines is crucial for the best prevention of fractures.
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Affiliation(s)
- Martine Cohen-Solal
- Department of Skeletal Diseases, INSERM U1132 & Université de Paris, Hôpital Lariboisière, Paris, France
- Correspondence should be addressed to M Cohen-Solal:
| | - Thomas Funck-Brentano
- Department of Skeletal Diseases, INSERM U1132 & Université de Paris, Hôpital Lariboisière, Paris, France
| | - Pablo Ureña Torres
- AURA Nord, Saint Ouen, France
- Department of Renal Physiology, Necker Hospital, Université de Paris, Paris, France
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19
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Bacchetta J, Bardet C, Prié D. Physiology of FGF23 and overview of genetic diseases associated with renal phosphate wasting. Metabolism 2020; 103S:153865. [PMID: 30664852 DOI: 10.1016/j.metabol.2019.01.006] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 01/08/2019] [Accepted: 01/16/2019] [Indexed: 12/31/2022]
Abstract
Phosphate is a cornerstone of several physiological pathways including skeletal development, bone mineralization, membrane composition, nucleotide structure, maintenance of plasma pH, and cellular signaling. The kidneys have a key role in phosphate homeostasis with three hormones having important functions in renal phosphate handling or intestinal absorption: parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and 1-25-dihydroxyvitamin D (1,25(OH)2D). FGF23 is mainly synthesized by osteocytes; it is a direct phosphaturic factor that also inhibits 1,25(OH)2D and PTH. In addition to crucial effects on phosphate and calcium metabolism, FGF23 also has 'off-target' effects notably on the cardiovascular, immune and central nervous systems. Genetic diseases may affect the FGF23 pathway, resulting in either increased FGF23 levels leading to hypophosphatemia (such as in X-linked hypophosphatemia) or defective secretion/action of intact FGF23 inducing hyperphosphatemia (such as in familial tumoral calcinosis). The aim of this review is to provide an overview of FGF23 physiology and pathophysiology in X-linked hypophosphatemia, with a focus on FGF23-associated genetic diseases.
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Affiliation(s)
- Justine Bacchetta
- Reference Center for Rare Renal Disorders, Reference Center for Rare Disorders of Calcium and Phosphate Metabolism, Department of Pediatric Nephrology, Rheumatology and Dermatology, Femme Mère Enfant Hospital, Bron Cedex, France; Lyon-Est Medical School, Lyon 1 University, Lyon, France; INSERM 1033, LYOS, Bone Disorders Prevention, Lyon, France.
| | - Claire Bardet
- Paris Descartes University, EA2496, Faculty of Dental Surgery, Montrouge, France
| | - Dominique Prié
- Paris Descartes University of Medicine, Necker-Enfants Malades Institute, INSERM U1151, France; Functional Exploration Department, Necker-Enfants Malades Hospital, AP-HP, Paris, France
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20
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Abstract
Calcium kidney stones are common worldwide. Most are idiopathic and composed of calcium oxalate. Calcium phosphate is present in around 80% and may initiate stone formation. Stone production is multifactorial with a polygenic genetic contribution. Phosphaturia is found frequently among stone formers but until recently received scant attention. This review examines possible mechanisms for the phosphaturia and its relevance to stone formation from a wide angle. There is a striking lack of clinical data. Phosphaturia is associated, but not correlated, with hypercalciuria, increased 1,25 dihydroxy-vitamin D [1,25 (OH)2D], and sometimes evidence of disturbances in proximal renal tubular function. Phosphate reabsorption in the proximal renal tubules requires tightly regulated interaction of many proteins. Paracellular flow through intercellular tight junctions is the major route of phosphate absorption from the intestine and can be reduced therapeutically in hyperphosphatemic patients. In monogenic defects stones develop when phosphaturia is associated with hypercalciuria, generally explained by increased 1,25 (OH)2D production in response to hypophosphatemia. Calcification does not occur in disorders with increased FGF23 when phosphaturia occurs in isolation and 1,25 (OH)2D is suppressed. Candidate gene studies have identified mutations in the phosphate transporters, but in few individuals. One genome-wide study identified a polymorphism of the phosphate transporter gene SLC34A4 associated with stones. Others did not find mutations obviously linked to phosphate reabsorption. Future genetic studies should have a wide trawl and should focus initially on groups of patients with clearly defined phenotypes. The global data should be pooled.
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Affiliation(s)
- Valerie Walker
- Department of Clinical Biochemistry, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
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21
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Alsaffar H, Beshyah S. Gulf X-linked hypophosphatemia preceptorship: July 4–6, 2019, Bicêtre Paris sud hospital, Paris, France. IBNOSINA JOURNAL OF MEDICINE AND BIOMEDICAL SCIENCES 2019. [DOI: 10.4103/ijmbs.ijmbs_69_19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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22
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Mills ES, Iorio L, Feinn RS, Duignan KM, Macica CM. Joint replacement in X-linked hypophosphatemia. J Orthop 2018; 16:55-60. [PMID: 30662239 DOI: 10.1016/j.jor.2018.12.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Accepted: 12/02/2018] [Indexed: 10/27/2022] Open
Abstract
X-linked hypophosphatemia (XLH) is associated with a pervasive, severe degenerative osteoarthritis. We conducted a retrospective chart review/patient survey using the Knee or Hip Osteoarthritis Outcome Score Physical Function Short Form. Fourteen total knee arthroplasties and 7 total hip arthroplasties among 11 patients were included. The mean KOOS-PS score was 31.4 ± 9.7 with a mean follow up of 6.9 years. Mean HOOS-PS score was 14.8 ± 12.9 at a mean follow up of 7.6 years. One knee failed due to aseptic loosening and one hip was revised due to polyethylene wear. In conclusion, total joint arthroplasty is beneficial in XLH.
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Affiliation(s)
- Emily S Mills
- Department of Medical Sciences, Frank H. Netter MD School of Medicine at Quinnipiac University, Hamden, CT, 06518, USA
| | - Louis Iorio
- Department of Medical Sciences, Frank H. Netter MD School of Medicine at Quinnipiac University, Hamden, CT, 06518, USA
| | - Richard S Feinn
- Department of Medical Sciences, Frank H. Netter MD School of Medicine at Quinnipiac University, Hamden, CT, 06518, USA
| | - Kevin M Duignan
- Department of Medical Sciences, Frank H. Netter MD School of Medicine at Quinnipiac University, Hamden, CT, 06518, USA
| | - Carolyn M Macica
- Department of Medical Sciences, Frank H. Netter MD School of Medicine at Quinnipiac University, Hamden, CT, 06518, USA
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23
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The Association of Fibroblast Growth Factor-23 with Mineral Factors (Ca, P, and Mg), Parathyroid Hormone, and 25-Hydroxyvitamin D in Hemodialysis Patients: A Multicenter Study. Nephrourol Mon 2018. [DOI: 10.5812/numonthly.84296] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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24
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Marcucci G, Masi L, Ferrarì S, Haffner D, Javaid MK, Kamenický P, Reginster JY, Rizzoli R, Brandi ML. Phosphate wasting disorders in adults. Osteoporos Int 2018; 29:2369-2387. [PMID: 30014155 DOI: 10.1007/s00198-018-4618-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 06/19/2018] [Indexed: 12/14/2022]
Abstract
A cause of hypophosphatemia is phosphate wasting disorders. Knowledge concerning mechanisms involved in phosphate wasting disorders has greatly increased in the last decade by the identification of phosphatonins, among them FGF-23. FGF-23 is a primarily bone derived factor decreasing renal tubular reabsorption of phosphate and the synthesis of calcitriol. Currently, pharmacological treatment of these disorders offers limited efficacy and is potentially associated to gastrointestinal, renal, and parathyroid complications; therefore, efforts have been directed toward newer pharmacological strategies that target the FGF-23 pathway. This review focuses on phosphate metabolism, its main regulators, and phosphate wasting disorders in adults, highlighting the main issues related to diagnosis and current and new potential treatments.
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Affiliation(s)
- G Marcucci
- Metabolic Bone Diseases Unit, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
| | - L Masi
- Metabolic Bone Diseases Unit, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
| | - S Ferrarì
- Division of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - D Haffner
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - M K Javaid
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - P Kamenický
- Service d'Endocrinologie et des Maladies de la Reproduction, Centre de référence des Maladies Rares du métabolisme du calcium et du phosphore, Hopital de Bicêtre - AP-HP, 94275, Le Kremlin-Bicêtre, France
| | - J-Y Reginster
- Department of Public Health, Epidemiology and Health Economics, University of Liège, Liège, Belgium
| | - R Rizzoli
- Division of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - M L Brandi
- Metabolic Bone Diseases Unit, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.
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25
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Durlacher-Betzer K, Hassan A, Levi R, Axelrod J, Silver J, Naveh-Many T. Interleukin-6 contributes to the increase in fibroblast growth factor 23 expression in acute and chronic kidney disease. Kidney Int 2018; 94:315-325. [PMID: 29861060 DOI: 10.1016/j.kint.2018.02.026] [Citation(s) in RCA: 118] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 02/18/2018] [Accepted: 02/22/2018] [Indexed: 12/13/2022]
Abstract
The high serum fibroblast growth factor 23 (FGF23) levels in patients with acute kidney injury (AKI) and chronic kidney disease (CKD) are associated with increased morbidity and mortality. Mice with folic acid-induced AKI had an increase in bone FGF23 mRNA expression together with an increase in serum FGF23 and several circulating cytokines including interleukin-6 (IL-6). Dexamethasone partially prevented the increase in IL-6 and FGF23 in the AKI mice. IL-6 knock-out mice fed an adenine diet to induce CKD failed to increase bone FGF23 mRNA and had a muted increase in serum FGF23 levels, compared with the increases in wild-type mice with CKD. Therefore, IL-6 contributes to the increase in FGF23 observed in CKD. Hydrodynamic tail injection of IL-6/soluble IL-6 receptor (sIL-6R) fusion protein hyper IL-6 (HIL-6) plasmid increased serum FGF23 levels. Circulating sIL-6R levels were increased in both CKD and AKI mice, suggesting that IL-6 increases FGF23 through sIL-6R-mediated trans-signaling. Renal IL-6 mRNA expression was increased in mice with either AKI or CKD, suggesting the kidney is the source for the increased serum IL-6 levels in the uremic state. HIL-6 also increased FGF23 mRNA in calvaria organ cultures and osteoblast-like UMR106 cells in culture, demonstrating a direct effect of IL-6 on FGF23 expression. HIL-6 increased FGF23 promoter activity through STAT3 phosphorylation and its evolutionarily conserved element in the FGF23 promoter. Thus, IL-6 increases FGF23 transcription and contributes to the high levels of serum FGF23 in both acute and chronic kidney disease.
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MESH Headings
- Acute Kidney Injury/blood
- Acute Kidney Injury/chemically induced
- Acute Kidney Injury/drug therapy
- Acute Kidney Injury/immunology
- Adenine/toxicity
- Animals
- Bone and Bones/pathology
- Dexamethasone/therapeutic use
- Disease Models, Animal
- Fibroblast Growth Factor-23
- Fibroblast Growth Factors/blood
- Fibroblast Growth Factors/genetics
- Fibroblast Growth Factors/immunology
- Fibroblast Growth Factors/metabolism
- Folic Acid/toxicity
- Glucocorticoids/therapeutic use
- Humans
- Interleukin-6/blood
- Interleukin-6/genetics
- Interleukin-6/immunology
- Interleukin-6/metabolism
- Kidney/immunology
- Kidney/pathology
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Phosphorylation/immunology
- Promoter Regions, Genetic/genetics
- RNA, Messenger/metabolism
- Receptors, Interleukin-6/genetics
- Recombinant Fusion Proteins/administration & dosage
- Recombinant Fusion Proteins/genetics
- Renal Insufficiency, Chronic/blood
- Renal Insufficiency, Chronic/chemically induced
- Renal Insufficiency, Chronic/drug therapy
- Renal Insufficiency, Chronic/immunology
- STAT3 Transcription Factor/metabolism
- Transcription, Genetic/immunology
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Affiliation(s)
- Karina Durlacher-Betzer
- Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Alia Hassan
- Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Ronen Levi
- Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Jonathan Axelrod
- Goldyn Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Justin Silver
- Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Tally Naveh-Many
- Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
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26
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Dhillon-Jhattu S, Sprague SM. Should phosphate management be limited to the KDIGO/ KDOQI guidelines? Semin Dial 2018; 31:377-381. [PMID: 29671909 DOI: 10.1111/sdi.12702] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Hyperphosphatemia is a common complication of CKD. Prior to development of overt hyperphosphatemia, there are several adaptive mechanisms that occur to maintain normal phosphorus equilibrium in patients with CKD. These include an early and progressive rise in fibroblast growth factor 23 (FGF 23), followed by an increase in parathyroid hormone (PTH) with a decrease in 1,25-dihydroxyvitamin D (1,25 Vit D). Over the last 20 years, a large number of studies have shown that hyperphosphatemia is a strong predictor of adverse clinical outcomes including increased incidence of vascular calcification, cardiovascular disease, and all-cause mortality in both individuals with CKD as well as those with normal kidney function. In addition, elevations of both FGF 23 and PTH are independently associated with increased morbidity and mortality. Therefore, phosphorus lowering therapies are a vital part of the treatment strategy for patients with CKD and include dietary phosphorus restriction, treatment with phosphate binders and removal with dialysis. However, there has been a lack of high quality evidence demonstrating beneficial effects of phosphate lowering therapy on clinical outcomes. Furthermore, we do not have definitive data as to whether effective phosphate control with phosphate binders will prevent elevations in FGF 23, and whether lowering FGF 23 levels will lead to improved patient outcomes. As a result of the presently available data (or lack thereof) clinical guidelines recommend treatment only after hyperphosphatemia develops and in dialysis patients; KDOQI recommends a treatment target of less than 5.5 mg/dL, whereas KDIGO recommends treating "towards normal." We are left with a clinical dilemma, being whether these recommendations are adequate, or should we be more aggressive in phosphate management. In this article, our goal is to discuss some of the studies concerning the adverse consequences of phosphate excess and as well as elevated FGF 23 levels, and present our opinion on what we believe the goal of treatment should be.
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Affiliation(s)
- Sangeet Dhillon-Jhattu
- NorthShore University HealthSystem and University of Chicago-Pritzker School of Medicine, Chicago, IL, USA
| | - Stuart M Sprague
- NorthShore University HealthSystem and University of Chicago-Pritzker School of Medicine, Chicago, IL, USA
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27
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Yamada S, Wallingford MC, Borgeia S, Cox TC, Giachelli CM. Loss of PiT-2 results in abnormal bone development and decreased bone mineral density and length in mice. Biochem Biophys Res Commun 2018; 495:553-559. [PMID: 29133259 PMCID: PMC5739526 DOI: 10.1016/j.bbrc.2017.11.071] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 11/10/2017] [Indexed: 01/31/2023]
Abstract
Normal bone mineralization requires phosphate oversaturation in bone matrix vesicles, as well as normal regulation of phosphate metabolism via the interplay among bone, intestine, and kidney. In turn, derangement of phosphate metabolism greatly affects bone function and structure. The type III sodium-dependent phosphate transporters, PiT-1 and PiT-2, are believed to be important in tissue phosphate metabolism and physiological bone formation, but their requirement and molecular roles in bone remain poorly investigated. In order to decipher the role of PiT-2 in bone, we examined normal bone development, growth, and mineralization in global PiT-2 homozygous knockout mice. PiT-2 deficiency resulted in reduced vertebral column, femur, and tibia length as well as mandibular dimensions. Micro-computed tomography analysis revealed that bone mineral density in the mandible, femur, and tibia were decreased, indicating that maintenance of bone function and structure is impaired in both craniofacial and long bones of PiT-2 deficient mice. Both cortical and trabecular thickness and mineral density were reduced in PiT-2 homozygous knockout mice compared with wild-type mice. These results suggest that PiT-2 is involved in normal bone development and growth and plays roles in cortical and trabecular bone metabolism feasibly by regulating local phosphate transport and mineralization processes in the bone. Further studies that evaluate bone cell-specific loss of PiT-2 are now warranted and may yield insight into complex mechanisms of bone development and growth, leading to identification of new therapeutic options for patients with bone diseases.
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Affiliation(s)
- Shunsuke Yamada
- Department of Bioengineering, University of Washington, Seattle, WA 98195, USA
| | - Mary C Wallingford
- Department of Bioengineering, University of Washington, Seattle, WA 98195, USA
| | - Suhaib Borgeia
- Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Timothy C Cox
- Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
| | - Cecilia M Giachelli
- Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
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28
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Pimentel A, Ureña-Torres P, Zillikens MC, Bover J, Cohen-Solal M. Fractures in patients with CKD—diagnosis, treatment, and prevention: a review by members of the European Calcified Tissue Society and the European Renal Association of Nephrology Dialysis and Transplantation. Kidney Int 2017; 92:1343-1355. [DOI: 10.1016/j.kint.2017.07.021] [Citation(s) in RCA: 110] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 07/12/2017] [Accepted: 07/17/2017] [Indexed: 01/29/2023]
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29
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Molina P, Carrero JJ, Bover J, Chauveau P, Mazzaferro S, Torres PU. Vitamin D, a modulator of musculoskeletal health in chronic kidney disease. J Cachexia Sarcopenia Muscle 2017; 8:686-701. [PMID: 28675610 PMCID: PMC5659055 DOI: 10.1002/jcsm.12218] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 04/04/2017] [Accepted: 04/20/2017] [Indexed: 02/06/2023] Open
Abstract
The spectrum of activity of vitamin D goes beyond calcium and bone homeostasis, and growing evidence suggests that vitamin D contributes to maintain musculoskeletal health in healthy subjects as well as in patients with chronic kidney disease (CKD), who display the combination of bone metabolism disorder, muscle wasting, and weakness. Here, we review how vitamin D represents a pathway in which bone and muscle may interact. In vitro studies have confirmed that the vitamin D receptor is present on muscle, describing the mechanisms whereby vitamin D directly affects skeletal muscle. These include genomic and non-genomic (rapid) effects, regulating cellular differentiation and proliferation. Observational studies have shown that circulating 25-hydroxyvitamin D levels correlate with the clinical symptoms and muscle morphological changes observed in CKD patients. Vitamin D deficiency has been linked to low bone formation rate and bone mineral density, with an increased risk of skeletal fractures. The impact of low vitamin D status on skeletal muscle may also affect muscle metabolic pathways, including its sensitivity to insulin. Although some interventional studies have shown that vitamin D may improve physical performance and protect against the development of histological and radiological signs of hyperparathyroidism, evidence is still insufficient to draw definitive conclusions.
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Affiliation(s)
- Pablo Molina
- Department of NephrologyHospital Universitario Doctor PesetValenciaSpain
- REDinRENMadridSpain
- Department of MedicineUniversitat de ValènciaValenciaSpain
| | - Juan J. Carrero
- Division of Renal MedicineCLINTEC, Karolinska InstitutetStockholmSweden
| | - Jordi Bover
- REDinRENMadridSpain
- Department of NephrologyFundació PuigvertBarcelonaSpain
- IIB Sant PauBarcelonaSpain
| | - Philippe Chauveau
- Service de Néphrologie Transplantation DialyseCentre Hospitalier Universitaire de Bordeaux et Aurad‐AquitaineBordeauxFrance
| | - Sandro Mazzaferro
- Department of Cardiovascular, Respiratory, Nephrologic and Geriatric SciencesSapienza University of RomeRomeItaly
| | - Pablo Ureña Torres
- Department of Nephrology and DialysisClinique du Landy, Ramsay‐Générale de SantéSaint OuenParisFrance
- Department of Renal PhysiologyNecker Hospital, University of Paris DescartesParisFrance
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30
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Chonchol M, Gitomer B, Isakova T, Cai X, Salusky I, Pereira R, Abebe K, Torres V, Steinman TI, Grantham JJ, Chapman AB, Schrier RW, Wolf M. Fibroblast Growth Factor 23 and Kidney Disease Progression in Autosomal Dominant Polycystic Kidney Disease. Clin J Am Soc Nephrol 2017; 12:1461-1469. [PMID: 28705885 PMCID: PMC5586583 DOI: 10.2215/cjn.12821216] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 05/26/2017] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND OBJECTIVES Increases in fibroblast growth factor 23 precede kidney function decline in autosomal dominant polycystic kidney disease; however, the role of fibroblast growth factor 23 in autosomal dominant polycystic kidney disease has not been well characterized. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS We measured intact fibroblast growth factor 23 levels in baseline serum samples from 1002 participants in the HALT-PKD Study A (n=540; mean eGFR =91±17 ml/min per 1.73 m2) and B (n=462; mean eGFR =48±12 ml/min per 1.73 m2). We used linear mixed and Cox proportional hazards models to test associations between fibroblast growth factor 23 and eGFR decline, percentage change in height-adjusted total kidney volume, and composite of time to 50% reduction in eGFR, onset of ESRD, or death. RESULTS Median (interquartile range) intact fibroblast growth factor 23 was 44 (33-56) pg/ml in HALT-PKD Study A and 69 (50-93) pg/ml in Study B. In adjusted models, annualized eGFR decline was significantly faster in the upper fibroblast growth factor 23 quartile (Study A: quartile 4, -3.62; 95% confidence interval, -4.12 to -3.12 versus quartile 1, -2.51; 95% confidence interval, -2.71 to -2.30 ml/min per 1.73 m2; P for trend <0.001; Study B: quartile 4, -3.74; 95% confidence interval, -4.14 to -3.34 versus quartile 1, -2.78; 95% confidence interval, -2.92 to -2.63 ml/min per 1.73 m2; P for trend <0.001). In Study A, higher fibroblast growth factor 23 quartiles were associated with greater longitudinal percentage increase in height-adjusted total kidney volume in adjusted models (quartile 4, 6.76; 95% confidence interval, 5.57 to 7.96 versus quartile 1, 6.04; 95% confidence interval, 5.55 to 6.54; P for trend =0.03). In Study B, compared with the lowest quartile, the highest fibroblast growth factor 23 quartile was associated with elevated risk for the composite outcome (hazard ratio, 3.11; 95% confidence interval, 1.84 to 5.25). Addition of fibroblast growth factor 23 to a model of annualized decline in eGFR≥3.0 ml/min per 1.73 m2 did not improve risk prediction. CONCLUSIONS Higher serum fibroblast growth factor 23 concentration was associated with kidney function decline, height-adjusted total kidney volume percentage increase, and death in patients with autosomal dominant polycystic kidney disease. However, fibroblast growth factor 23 did not substantially improve prediction of rapid kidney function decline.
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Affiliation(s)
- Michel Chonchol
- Due to the number of contributing authors, the affiliations are provided in the Supplemental Material
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31
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Yuan Q, Xiong QC, Gupta M, López-Pintor RM, Chen XL, Seriwatanachai D, Densmore M, Man Y, Gong P. Dental implant treatment for renal failure patients on dialysis: a clinical guideline. Int J Oral Sci 2017; 9:125-132. [PMID: 28644432 PMCID: PMC5709544 DOI: 10.1038/ijos.2017.23] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/17/2017] [Indexed: 02/05/2023] Open
Abstract
Chronic kidney disease (CKD) is a worldwide public health problem that is growing in prevalence and is associated with severe complications. During the progression of the disease, a majority of CKD patients suffer oral complications. Dental implants are currently the most reliable and successful treatment for missing teeth. However, due to complications of CKD such as infections, bone lesions, bleeding risks, and altered drug metabolism, dental implant treatment for renal failure patients on dialysis is more challenging. In this review, we have summarized the characteristics of CKD and previous publications regarding dental treatments for renal failure patients. In addition, we discuss our recent research results and clinical experience in order to provide dental implant practitioners with a clinical guideline for dental implant treatment for renal failure patients undergoing hemodialysis.
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Affiliation(s)
- Quan Yuan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Qiu-Chan Xiong
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Megha Gupta
- Department of Preventive Dental Sciences, Division of Pedodontics, College of Dentistry, Al-Showajra Academic Campus, Jazan University, Gizan, Kingdom of Saudi Arabia
| | - Rosa María López-Pintor
- Department of Oral Medicine and Surgery, School of Dentistry, Complutense University, Madrid, Spain
| | - Xiao-Lei Chen
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China
| | | | - Michael Densmore
- Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, USA
| | - Yi Man
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ping Gong
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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32
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α-Klotho expression determines nitric oxide synthesis in response to FGF-23 in human aortic endothelial cells. PLoS One 2017; 12:e0176817. [PMID: 28463984 PMCID: PMC5413063 DOI: 10.1371/journal.pone.0176817] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 04/18/2017] [Indexed: 01/03/2023] Open
Abstract
Endothelial cells (ECs) express fibroblast growth factor (FGF) receptors and are metabolically active after treatment with FGF-23. It is not known if this effect is α-Klotho independent or mediated by humoral or endogenous endothelial α-Klotho. In the present study, we aimed to characterize EC α-Klotho expression within the human vascular tree and to investigate the potential role of α-Klotho in determining FGF-23 mediated EC regulation. Human tissue and ECs from various organs were used for immunohistochemistry and Western blot. Primary cultures of human aortic endothelial cells (HAECs) and human brain microvascular endothelial cells (HBMECs) were used to generate in vitro cell models. We found endogenous α-Klotho expression in ECs from various organs except in microvascular ECs from human brain. Furthermore, FGF-23 stimulated endothelial nitric oxide synthase (eNOS) expression, nitric oxide (NO) production, and cell proliferation in HAECs. Interestingly, these effects were not observed in our HBMEC model in vitro. High phosphate treatment and endothelial α-Klotho knockdown mitigated FGF-23 mediated eNOS induction, NO production, and cell proliferation in HAECs. Rescue treatment with soluble α-Klotho did not reverse endothelial FGF-23 resistance caused by reduced or absent α-Klotho expression in HAECs. These novel observations provide evidence for differential α-Klotho functional expression in the human endothelium and its presence may play a role in determining the response to FGF-23 in the vascular tree. α-Klotho was not detected in cerebral microvascular ECs and its absence may render these cells nonresponsive to FGF-23.
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Rousseaud A, Moriceau S, Ramos-Brossier M, Oury F. Bone-brain crosstalk and potential associated diseases. Horm Mol Biol Clin Investig 2017; 28:69-83. [PMID: 27626767 DOI: 10.1515/hmbci-2016-0030] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Accepted: 07/11/2016] [Indexed: 12/24/2022]
Abstract
Reciprocal relationships between organs are essential to maintain whole body homeostasis. An exciting interplay between two apparently unrelated organs, the bone and the brain, has emerged recently. Indeed, it is now well established that the brain is a powerful regulator of skeletal homeostasis via a complex network of numerous players and pathways. In turn, bone via a bone-derived molecule, osteocalcin, appears as an important factor influencing the central nervous system by regulating brain development and several cognitive functions. In this paper we will discuss this complex and intimate relationship, as well as several pathologic conditions that may reinforce their potential interdependence.
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Courbebaisse M, Mehel H, Petit-Hoang C, Ribeil JA, Sabbah L, Tuloup-Minguez V, Bergerat D, Arlet JB, Stanislas A, Souberbielle JC, Le Clésiau H, Fischmeister R, Friedlander G, Prié D. Carboxy-terminal fragment of fibroblast growth factor 23 induces heart hypertrophy in sickle cell disease. Haematologica 2016; 102:e33-e35. [PMID: 27789679 DOI: 10.3324/haematol.2016.150987] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Affiliation(s)
- Marie Courbebaisse
- Université Paris Descartes, Sorbonne-Paris-Cité, Faculté de Médecine, Paris.,INSERM U1151-CNRS UMR8253, Paris.,Service de Physiologie Explorations Fonctionnelles Hôpital Necker-Enfants Malades Assistance Publique-Hôpitaux de Paris.,Service de Physiologie Explorations Fonctionnelles Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris
| | | | | | - Jean-Antoine Ribeil
- Département de Biothérapie, Hôpital Necker-Enfants Malades Assistance Publique-Hôpitaux de Paris
| | - Laurent Sabbah
- Unité Fonctionnelle de Cardiologie Adultes, Hôpital Necker-Enfants Malades Assistance Publique-Hôpitaux de Paris
| | | | | | - Jean-Benoit Arlet
- Service de Médecine Interne, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris.,INSERM U1163, CNRS 8254, Institut IMAGINE, Paris
| | - Aurélie Stanislas
- Département de Biothérapie, Hôpital Necker-Enfants Malades Assistance Publique-Hôpitaux de Paris
| | - Jean-Claude Souberbielle
- INSERM U1151-CNRS UMR8253, Paris.,Service de Physiologie Explorations Fonctionnelles Hôpital Necker-Enfants Malades Assistance Publique-Hôpitaux de Paris
| | - Hervé Le Clésiau
- Centre de Santé et d'Assurance Maladie Agence de Seine-Saint-Denis, Bobigny, France
| | - Rodolphe Fischmeister
- INSERM UMR-S 1180 Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
| | - Gérard Friedlander
- Université Paris Descartes, Sorbonne-Paris-Cité, Faculté de Médecine, Paris.,INSERM U1151-CNRS UMR8253, Paris.,Service de Physiologie Explorations Fonctionnelles Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris
| | - Dominique Prié
- Université Paris Descartes, Sorbonne-Paris-Cité, Faculté de Médecine, Paris .,INSERM U1151-CNRS UMR8253, Paris.,Service de Physiologie Explorations Fonctionnelles Hôpital Necker-Enfants Malades Assistance Publique-Hôpitaux de Paris
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Sakoh T, Nakayama M, Tsuchihashi T, Yoshitomi R, Tanaka S, Katafuchi E, Fukui A, Shikuwa Y, Anzai N, Kitazono T, Tsuruya K. Associations of fibroblast growth factor 23 with urate metabolism in patients with chronic kidney disease. Metabolism 2016; 65:1498-507. [PMID: 27621185 DOI: 10.1016/j.metabol.2016.07.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 06/13/2016] [Accepted: 07/14/2016] [Indexed: 10/21/2022]
Abstract
OBJECTIVE In patients with preserved kidney function, a positive association of fibroblast growth factor 23 (FGF23) with serum uric acid (SUA) has been reported; however, the relationship in overall chronic kidney disease (CKD) patients has not been investigated. No report has examined the relationship between FGF23 and uric acid clearance (CUA). The aim of the present study was to determine whether FGF23 is independently associated with urate metabolism in patients with CKD stages 1-5. MATERIALS AND METHODS In this cross-sectional study, 537 CKD patients were enrolled. SUA, CUA, FGF23, parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured. Multivariable linear regression analysis was applied to determine independent factors associated with SUA or CUA. RESULTS In all patients, both SUA and CUA were independently associated with male sex, use of diuretics, use of uric acid-lowering agents, estimated glomerular filtration rate, and log FGF23 (β=0.29, P<0.01 for SUA; β=-0.11, P<0.01 for CUA), but not with log PTH or log 1,25(OH)2D. Dyslipidemia and diabetes were also independent factors for SUA and CUA, respectively. In multivariable analyses by sex, log FGF23 was associated with SUA in both sexes (β=0.32, P<0.01 in males vs. β=0.20, P=0.02 in females). Conversely, log FGF23 was independently associated with CUA in males (β=-0.15, P<0.01), but not in females (β=-0.09, P=0.17). CONCLUSIONS FGF23 was independently associated with urate metabolism in this population of CKD patients. FGF23 might also have a stronger association with urate metabolism in males compared with females.
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Affiliation(s)
- Teppei Sakoh
- Division of Nephrology and Clinical Research Institute, Department of Internal Medicine, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-ku, Fukuoka 810-8563, Japan; Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Masaru Nakayama
- Division of Nephrology and Clinical Research Institute, Department of Internal Medicine, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-ku, Fukuoka 810-8563, Japan.
| | - Takuya Tsuchihashi
- Division of Hypertension, Department of Internal Medicine, Steel Memorial Yawata Hospital, 1-1-1 Harunomachi, Yahatahigashi-ku, Fukuoka 805-8508, Japan.
| | - Ryota Yoshitomi
- Division of Nephrology and Clinical Research Institute, Department of Internal Medicine, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-ku, Fukuoka 810-8563, Japan; Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Shigeru Tanaka
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Internal Medicine, Fukuoka Dental College, 2-15-1 Tamura, Sawara-ku, Fukuoka 814-0193, Japan.
| | - Eisuke Katafuchi
- Division of Nephrology and Clinical Research Institute, Department of Internal Medicine, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-ku, Fukuoka 810-8563, Japan.
| | - Akiko Fukui
- Division of Nephrology and Clinical Research Institute, Department of Internal Medicine, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-ku, Fukuoka 810-8563, Japan.
| | - Yui Shikuwa
- Division of Nephrology and Clinical Research Institute, Department of Internal Medicine, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-ku, Fukuoka 810-8563, Japan.
| | - Naohiko Anzai
- Department of Pharmacology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Takanari Kitazono
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Kazuhiko Tsuruya
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Integrated Therapy for Chronic Kidney Disease, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
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Sharaf El Din UAA, Salem MM, Abdulazim DO. Vascular calcification: When should we interfere in chronic kidney disease patients and how? World J Nephrol 2016; 5:398-417. [PMID: 27648404 PMCID: PMC5011247 DOI: 10.5527/wjn.v5.i5.398] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 04/20/2016] [Accepted: 06/27/2016] [Indexed: 02/06/2023] Open
Abstract
Chronic kidney disease (CKD) patients are endangered with the highest mortality rate compared to other chronic diseases. Cardiovascular events account for up to 60% of the fatalities. Cardiovascular calcifications affect most of the CKD patients. Most of this calcification is related to disturbed renal phosphate handling. Fibroblast growth factor 23 and klotho deficiency were incriminated in the pathogenesis of vascular calcification through different mechanisms including their effects on endothelium and arterial wall smooth muscle cells. In addition, deficient klotho gene expression, a constant feature of CKD, promotes vascular pathology and shares in progression of the CKD. The role of gut in the etio-pathogenesis of systemic inflammation and vascular calcification is a newly discovered mechanism. This review will cover the medical history, prevalence, pathogenesis, clinical relevance, different tools used to diagnose, the ideal timing to prevent or to withhold the progression of vascular calcification and the different medications and medical procedures that can help to prolong the survival of CKD patients.
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Adema AY, de Jong MA, de Borst MH, Ter Wee PM, Vervloet MG. Phosphate Binding Therapy to Lower Serum Fibroblast-Growth-Factor-23 Concentrations in Chronic Kidney Disease: Rationale and Study Design of the Sevelamer on FGF23 Trial (SoFT). Nephron Clin Pract 2016; 134:215-220. [PMID: 27442253 DOI: 10.1159/000448184] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Accepted: 07/02/2016] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Increased levels of phosphate and fibroblast growth factor-23 (FGF23) are strong predictors of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Preliminary data suggest that interventions lowering gastro-intestinal phosphate uptake lowers serum FGF23 concentrations and improves cardiovascular risk and subsequently survival. However, data are lacking about the magnitude of effects, the effect in different stages of CKD and whether there is a dose-effect relationship. METHODS Therefore, the Sevelamer on FGF23 Trial (SoFT) is designed as an open-label, single-arm, clinical pilot study aiming to demonstrate the feasibility of a phosphate-restricted diet in combination with the phosphate binder sevelamer to induce an effective, predictable and sustained decrease in FGF23 level in patients with an estimated glomerular filtration rate (eGFR) of 15-90 or >90 ml/min/1.73 m2 with proteinuria >1.0 g in 24 h urine collection, despite optimally dosed RAAS blockade, without inducing hypophosphatemia using a forced uptitration treatment regimen aimed at restricting phosphate uptake.
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Tan SJ, Smith ER, Hewitson TD, Holt SG, Toussaint ND. The importance of klotho in phosphate metabolism and kidney disease. Nephrology (Carlton) 2016; 19:439-49. [PMID: 24750549 DOI: 10.1111/nep.12268] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/14/2014] [Indexed: 12/19/2022]
Abstract
The discovery of fibroblast growth factor-23 (FGF23) and its co-receptor α-klotho has broadened our understanding of mineral metabolism and led to a renewed research focus on phosphate homeostatic pathways in kidney disease. Expanding knowledge of these mechanisms, both in normal physiology and in pathology, identifies targets for potential interventions designed to reduce the complications of renal disease, particularly the cardiovascular sequelae. FGF23 has emerged as a major α-klotho-dependent endocrine regulator of mineral metabolism, functioning to activate vitamin D and as a phosphatonin. However, increasingly there is an appreciation that klotho may act independently as a phosphate regulator, as well as having significant activity in other key biological processes. This review outlines our current understanding of klotho, and its potential contribution to kidney disease and cardiovascular health.
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Affiliation(s)
- Sven-Jean Tan
- Department of Nephrology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia; Department of Medicine (RMH), The University of Melbourne, Melbourne, Victoria, Australia
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Mizuno M, Mitchell JH, Crawford S, Huang CL, Maalouf N, Hu MC, Moe OW, Smith SA, Vongpatanasin W. High dietary phosphate intake induces hypertension and augments exercise pressor reflex function in rats. Am J Physiol Regul Integr Comp Physiol 2016; 311:R39-48. [PMID: 27170660 PMCID: PMC4967233 DOI: 10.1152/ajpregu.00124.2016] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 05/06/2016] [Indexed: 01/14/2023]
Abstract
An increasing number of studies have linked high dietary phosphate (Pi) intake to hypertension. It is well established that the rise in sympathetic nerve activity (SNA) and blood pressure (BP) during physical exertion is exaggerated in many forms of hypertension, which are primarily mediated by an overactive skeletal muscle exercise pressor reflex (EPR). However, it remains unknown whether high dietary Pi intake potentiates the EPR-mediated SNA and BP response to exercise. Accordingly, we measured renal SNA (RSNA) and mean BP (MBP) in normotensive Sprague-Dawley rats fed a normal Pi diet (0.6%, n = 13) or high Pi diet (1.2%, n = 13) for 3 mo. As previously reported, we found that resting BP was significantly increased by 1.2% Pi diet in both conscious and anesthetized animals. Activation of the EPR by electrically induced hindlimb contraction triggered greater increases in ΔRSNA and ΔMBP in the 1.2% compared with 0.6% Pi group (126 ± 25 vs. 42 ± 9%; 44 ± 5 vs. 14 ± 2 mmHg, respectively, P < 0.01). Activation of the muscle mechanoreflex, a component of the EPR, by passively stretching hindlimb muscle also evoked greater increases in ΔRSNA and ΔMBP in the 1.2% compared with 0.6% Pi group (109 ± 27 vs. 24 ± 7%, 38 ± 7 vs. 8 ± 2 mmHg, respectively, P < 0.01). A similar response was produced by hindlimb intra-arterial capsaicin administration to stimulate the metaboreflex arm of the EPR. Thus, our data demonstrate a novel action of dietary Pi loading in augmenting EPR function through overactivation of both the muscle mechanoreflex and metaboreflex.
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Affiliation(s)
- Masaki Mizuno
- Department of Health Care Sciences, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Cardiology Division, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jere H Mitchell
- Cardiology Division, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Scott Crawford
- Department of Health Care Sciences, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Chou-Long Huang
- Nephrology Division, University of Texas Southwestern Medical Center, Dallas, Texas; Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Naim Maalouf
- Mineral Metabolism Division, University of Texas Southwestern Medical Center, Dallas, Texas; and Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Ming-Chang Hu
- Mineral Metabolism Division, University of Texas Southwestern Medical Center, Dallas, Texas; and Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Orson W Moe
- Nephrology Division, University of Texas Southwestern Medical Center, Dallas, Texas; Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Scott A Smith
- Department of Health Care Sciences, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Cardiology Division, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Wanpen Vongpatanasin
- Cardiology Division, University of Texas Southwestern Medical Center, Dallas, Texas; Hypertension Section, University of Texas Southwestern Medical Center, Dallas, Texas; Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas
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Wolf M. Mineral (Mal)Adaptation to Kidney Disease--Young Investigator Award Address: American Society of Nephrology Kidney Week 2014. Clin J Am Soc Nephrol 2015; 10:1875-85. [PMID: 26350436 PMCID: PMC4594069 DOI: 10.2215/cjn.04430415] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In the short time since its initial discovery as the cause of rare hypophosphatemic disorders, fibroblast growth factor-23 (FGF-23) has emerged as a major regulator of mineral metabolism and critical component of the bone and mineral adaptation to CKD. However, because elevated FGF-23 levels are also a novel biomarker and possible molecular mediator of increased risks of cardiovascular disease and death in CKD, the initially adaptive response to increase FGF-23 levels to maintain neutral phosphate balance in CKD may ultimately become maladaptive. Incorporating FGF-23 into understanding the complex physiology that governs normal bone and mineral metabolism and its alterations in CKD has filled critical knowledge gaps and opened a new landscape of exciting hypotheses and novel therapeutic strategies to be tested in the continued quest to alleviate the burden of CKD.
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Affiliation(s)
- Myles Wolf
- Division of Nephrology and Hypertension, Department of Medicine, and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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Functional role of inorganic trace elements in angiogenesis—Part I: N, Fe, Se, P, Au, and Ca. Crit Rev Oncol Hematol 2015; 96:129-42. [DOI: 10.1016/j.critrevonc.2015.05.010] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Revised: 04/15/2015] [Accepted: 05/12/2015] [Indexed: 01/08/2023] Open
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Razali NN, Hwu TT, Thilakavathy K. Phosphate homeostasis and genetic mutations of familial hypophosphatemic rickets. J Pediatr Endocrinol Metab 2015; 28:1009-17. [PMID: 25894638 DOI: 10.1515/jpem-2014-0366] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Accepted: 02/26/2015] [Indexed: 01/17/2023]
Abstract
Hypophosphatemic rickets (HR) is a syndrome of hypophosphatemia and rickets that resembles vitamin D deficiency, which is caused by malfunction of renal tubules in phosphate reabsorption. Phosphate is an essential mineral, which is important for bone and tooth structure. It is regulated by parathyroid hormone, 1,25-dihydroxyvitamin D and fibroblast-growth-factor 23 (FGF23). X-linked hypophosphatemia (XLH), autosomal dominant HR (ADHR), and autosomal recessive HR (ARHR) are examples of hereditary forms of HR, which are mainly caused by mutations in the phosphate regulating endopeptidase homolog, X-linked (PHEX), FGF23, and, dentin matrix protein-1 (DMP1) and ecto-nucleotide pyro phosphatase/phosphodiesterase 1 (ENPP1) genes, respectively. Mutations in these genes are believed to cause elevation of circulating FGF23 protein. Increase in FGF23 disrupts phosphate homeostasis, leading to HR. This review aims to summarize phosphate homeostasis and focuses on the genes and mutations related to XLH, ADHR, and ARHR. A compilation of XLH mutation hotspots based on the PHEX gene database and mutations found in the FGF23, DMP1, and ENPP1 genes are also made available in this review.
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Abstract
In the past 15 years, the field of physiology has been radically challenged by landmark studies using novel tools of genetic engineering. Particular to our interest, the reciprocal interactions between the skeleton and the nervous system were shown to be major ones. The demonstration that brain, via multiple pathways, is a powerful regulator of bone growth, has shed light on an important central regulation of skeletal homeostasis. More recently, it was shown that bone might return the favor to the brain through the secretion of a bone-derived hormone, osteocalcin. The skeleton influences development and cognitive functions of the central nervous system at different stages throughout life suggesting an intimate dialogue between bone and brain.
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Affiliation(s)
- Alexandre Chamouni
- Centre de Médecine Moléculaire, Institut Necker-Enfants Malades (INEM), 75014, Paris, France
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Effect of High-Flux Dialysis on Circulating FGF-23 Levels in End-Stage Renal Disease Patients: Results from a Randomized Trial. PLoS One 2015; 10:e0128079. [PMID: 26024521 PMCID: PMC4449206 DOI: 10.1371/journal.pone.0128079] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 04/21/2015] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND In patients undergoing maintenance hemodialysis (HD), increased levels of circulating fibroblast growth factor-23 (FGF-23) are independently associated with cardiovascular events and mortality. Interventional strategies aiming to reduce levels of FGF-23 in HD patients are of particular interest. The purpose of the current study was to compare the impact of high-flux versus low-flux HD on circulating FGF-23 levels. METHODS We conducted a post-hoc analysis of the MINOXIS study, including 127 dialysis patients randomized to low-flux (n = 62) and high-flux (n = 65) HD for 52 weeks. Patients with valid measures for FGF-23 investigated baseline and after 52 weeks were included. RESULTS Compared to baseline, a significant increase in FGF-23 levels after one year of low-flux HD was observed (Delta plasma FGF-23: +4026 RU/ml; p < 0.001). In contrast, FGF-23 levels remained stable in the high flux group (Delta plasma FGF-23: +373 RU/ml, p = 0.70). The adjusted difference of the absolute change in FGF-23 levels between the two treatment groups was statistically significant (p < 0.01). CONCLUSIONS Over a period of 12 months, high-flux HD was associated with stable FGF-23 levels, whereas the low-flux HD group showed an increase of FGF-23. However, the implications of the different FGF 23 time-trends in patients on high flux dialysis, as compared to the control group, remain to be explored in specifically designed clinical trials. TRIAL REGISTRATION German Clinical Trials Register (DRKS) DRKS00007612.
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Labonté ED, Carreras CW, Leadbetter MR, Kozuka K, Kohler J, Koo-McCoy S, He L, Dy E, Black D, Zhong Z, Langsetmo I, Spencer AG, Bell N, Deshpande D, Navre M, Lewis JG, Jacobs JW, Charmot D. Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD. J Am Soc Nephrol 2014; 26:1138-49. [PMID: 25404658 DOI: 10.1681/asn.2014030317] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Accepted: 07/23/2014] [Indexed: 02/02/2023] Open
Abstract
In CKD, phosphate retention arising from diminished GFR is a key early step in a pathologic cascade leading to hyperthyroidism, metabolic bone disease, vascular calcification, and cardiovascular mortality. Tenapanor, a minimally systemically available inhibitor of the intestinal sodium-hydrogen exchanger 3, is being evaluated in clinical trials for its potential to (1) lower gastrointestinal sodium absorption, (2) improve fluid overload-related symptoms, such as hypertension and proteinuria, in patients with CKD, and (3) reduce interdialytic weight gain and intradialytic hypotension in ESRD. Here, we report the effects of tenapanor on dietary phosphorous absorption. Oral administration of tenapanor or other intestinal sodium-hydrogen exchanger 3 inhibitors increased fecal phosphorus, decreased urine phosphorus excretion, and reduced [(33)P]orthophosphate uptake in rats. In a rat model of CKD and vascular calcification, tenapanor reduced sodium and phosphorus absorption and significantly decreased ectopic calcification, serum creatinine and serum phosphorus levels, circulating phosphaturic hormone fibroblast growth factor-23 levels, and heart mass. These results indicate that tenapanor is an effective inhibitor of dietary phosphorus absorption and suggest a new approach to phosphate management in renal disease and associated mineral disorders.
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Affiliation(s)
| | | | | | | | | | | | - Limin He
- Ardelyx, Inc., Fremont, California
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Abstract
Recent studies of inherited disorders of phosphate metabolism have shed new light on the understanding of phosphate metabolism. Phosphate has important functions in the body and several mechanisms have evolved to regulate phosphate balance including vitamin D, parathyroid hormone and phosphatonins such as fibroblast growth factor-23 (FGF23). Disorders of phosphate homeostasis leading to hypo- and hyperphosphataemia are common and have clinical and biochemical consequences. Notably, recent studies have linked hyperphosphataemia with an increased risk of cardiovascular disease. This review outlines the recent advances in the understanding of phosphate homeostasis and describes the causes, investigation and management of hypo- and hyperphosphataemia.
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Affiliation(s)
- P Manghat
- Department of Chemical Pathology, Darent Valley Hospital, Dartford, UK
| | - R Sodi
- Department of Biochemistry, NHS Lanarkshire, East Kilbride, UK
| | - R Swaminathan
- Department of Chemical Pathology, St. Thomas Hospital, London, UK
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Yamada S, Tsuruya K, Tokumoto M, Yoshida H, Hasegawa S, Tanaka S, Eriguchi M, Nakano T, Masutani K, Ooboshi H, Kitazono T. Fibroblast growth factor 23, but not parathyroid hormone, is associated with urinary phosphate regulation in patients on peritoneal dialysis. Ther Apher Dial 2014; 19:73-80. [PMID: 25195562 DOI: 10.1111/1744-9987.12221] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Fibroblast growth factor (FGF) 23 plays an important role in regulation of renal phosphate excretion in patients with chronic kidney disease. However, it remains undetermined whether FGF23 is closely linked to renal phosphate handling in patients with low glomerular filtration rate (GFR). The present cross-sectional study included 52 outpatients undergoing peritoneal dialysis with urine volume ≥ 100 mL/day. The primary outcome was level of urinary phosphate excretion, and the secondary outcomes were tubular maximal reabsorption of phosphate normalized to GFR (TmP/GFR), an index of the renal threshold for phosphate excretion, and level of peritoneal phosphate excretion. Variates of interest were serum FGF23 and parathyroid hormone (PTH) levels. The median and interquartile range of serum FGF23 level, TmP/GFR, and total urinary and peritoneal phosphate excretion were 5610 (1493-11 430) ng/mL, 1.30 (0.44-1.86) mg/dL, 117 (40-234) mg/day, and 208 (156-250) mg/day, respectively. Multivariate linear regression analysis revealed that serum FGF23 level was significantly (P < 0.05) associated with TmP/GFR negatively and significantly (P < 0.05) associated with urinary phosphate excretion positively, even after adjusting for confounders. In contrast, none of the three outcome variates was associated with serum PTH level. Neither serum FGF23 nor PTH level was associated with peritoneal phosphate excretion. The present study indicates that FGF23, but not PTH, is involved in urinary phosphate regulation, even in patients on peritoneal dialysis with residual renal function.
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Affiliation(s)
- Shunsuke Yamada
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Division of Internal Medicine, Fukuoka Dental College, Fukuoka, Japan
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48
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Létourneau-Montminy MP, Lovatto PA, Pomar C. Apparent total tract digestibility of dietary calcium and phosphorus and their efficiency in bone mineral retention are affected by body mineral status in growing pigs. J Anim Sci 2014; 92:3914-24. [PMID: 25057034 DOI: 10.2527/jas.2013-7320] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Improving dietary P utilization without modifying pig performance is crucial for production sustainability. A feeding program comprising three 28-d phases (20 to 40, 40 to 70, and 70 to 100 kg) was used to feed 72 pigs with an initial BW of 20 kg. The ability of the pigs to modify the digestive and metabolic utilization of P when fed either a control (CON) diet or a low-P (LOW) diet providing 40% less digestible P with a constant Ca:digestible P was studied using different sequences of dietary P and Ca restriction (i.e., depletion [LOW]) and recovery (i.e., repletion [CON]), namely CON-CON-CON, CON-CON-LOW, CON-LOW-LOW, LOW-CON-CON, LOW-LOW-CON, and LOW-LOW-LOW. Bone mineral content (BMC) was measured in the lumbar region (L2-L4) by dual-energy X-ray absorptiometry at the beginning and end of each feeding phase. Total feces and urine were collected during phases 2 and 3. At the end of phase 1, BMC was lower in the LOW pigs than in the C pigs (29%; P < 0.001). During phase 2, the BMC gain was greater in the LOW-CON pigs than in the CON-CON pigs (16%; P < 0.001). During phase 3, the LOW-LOW-CON pigs absorbed 26% more Ca (P < 0.001) and retained 56% more BMC (P < 0.001) than the CON-CON-CON pigs did. Digestive and metabolic adaptations allowed the LOW-LOW-CON and LOW-CON-CON pigs to reach BMC similar to that of the CON-CON-CON pigs. These metabolic adaptations are promising, but practical applications of these results requires a better understanding of the underlying mechanisms to fine-tune the degree of depletion, pig age, and the duration of P and Ca depletion and repletion periods.
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Affiliation(s)
- M P Létourneau-Montminy
- Agriculture and Agri-Food Canada, Dairy and Swine Research and Development Centre, Sherbrooke, QC, J1M 1Z3, Canada
| | - P A Lovatto
- Departamento de Zootecnia, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
| | - C Pomar
- Agriculture and Agri-Food Canada, Dairy and Swine Research and Development Centre, Sherbrooke, QC, J1M 1Z3, Canada
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Di Marco GS, Reuter S, Kentrup D, Grabner A, Amaral AP, Fobker M, Stypmann J, Pavenstädt H, Wolf M, Faul C, Brand M. Treatment of established left ventricular hypertrophy with fibroblast growth factor receptor blockade in an animal model of CKD. Nephrol Dial Transplant 2014; 29:2028-35. [PMID: 24875663 DOI: 10.1093/ndt/gfu190] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Activation of fibroblast growth factor receptor (FGFR)-dependent signalling by FGF23 may contribute to the complex pathogenesis of left ventricular hypertrophy (LVH) in chronic kidney disease (CKD). Pan FGFR blockade by PD173074 prevented development of LVH in the 5/6 nephrectomy rat model of CKD, but its ability to treat and reverse established LVH is unknown. METHODS CKD was induced in rats by 5/6 nephrectomy. Two weeks later, rats began treatment with vehicle (0.9% NaCl) or PD173074, 1 mg/kg once-daily for 3 weeks. Renal function was determined by urine and blood analyses. Left ventricular (LV) structure and function were determined by echocardiography, histopathology, staining for myocardial fibrosis (Sirius-Red) and investigating cardiac gene expression profiles by real-time PCR. RESULTS Two weeks after inducing CKD by 5/6 nephrectomy, rats manifested higher (mean ± SEM) systolic blood pressure (208 ± 4 versus 139 ± 3 mmHg; P < 0.01), serum FGF23 levels (1023 ± 225 versus 199 ± 9 pg/mL; P < 0.01) and LV mass (292 ± 9 versus 220 ± 3 mg; P < 0.01) when compared with sham-operated animals. Thereafter, 3 weeks of treatment with PD173074 compared with vehicle did not significantly change blood pressure, kidney function or metabolic parameters, but significantly reduced LV mass (230 ± 14 versus 341 ± 33 mg; P < 0.01), myocardial fibrosis (2.5 ± 0.7 versus 5.4 ± 0.95% staining/field; P < 0.01) and cardiac expression of genes associated with pathological LVH, while significantly increasing ejection fraction (18 versus 2.5% post-treatment increase; P < 0.05). CONCLUSIONS FGFR blockade improved cardiac structure and function in 5/6 nephrectomy rats with previously established LVH. These data support FGFR activation as a potentially modifiable, blood pressure-independent molecular mechanism of LVH in CKD.
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Affiliation(s)
- Giovana Seno Di Marco
- Department of Internal Medicine D, University Hospital Münster, Münster, North Rhine-Westphalia, Germany
| | - Stefan Reuter
- Department of Internal Medicine D, University Hospital Münster, Münster, North Rhine-Westphalia, Germany
| | - Dominik Kentrup
- Department of Internal Medicine D, University Hospital Münster, Münster, North Rhine-Westphalia, Germany
| | - Alexander Grabner
- Department of Internal Medicine D, University Hospital Münster, Münster, North Rhine-Westphalia, Germany Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Ansel Philip Amaral
- Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Manfred Fobker
- Centre for Laboratory Medicine, University Hospital Münster, Münster, North Rhine-Westphalia, Germany
| | - Jörg Stypmann
- Department of Cardiovascular Medicine, Division of Cardiology, University Hospital Münster, Münster, North Rhine-Westphalia, Germany
| | - Hermann Pavenstädt
- Department of Internal Medicine D, University Hospital Münster, Münster, North Rhine-Westphalia, Germany
| | - Myles Wolf
- Division of Nephrology and Hypertension, Department of Medicine, Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Christian Faul
- Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Marcus Brand
- Department of Internal Medicine D, University Hospital Münster, Münster, North Rhine-Westphalia, Germany
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50
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Six I, Okazaki H, Gross P, Cagnard J, Boudot C, Maizel J, Drueke TB, Massy ZA. Direct, acute effects of Klotho and FGF23 on vascular smooth muscle and endothelium. PLoS One 2014; 9:e93423. [PMID: 24695641 PMCID: PMC3973676 DOI: 10.1371/journal.pone.0093423] [Citation(s) in RCA: 90] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Accepted: 03/06/2014] [Indexed: 02/07/2023] Open
Abstract
Chronic kidney disease (CKD) is regarded as a state of Klotho deficiency and FGF23 excess. In patients with CKD a strong association has been found between increased serum FGF23 and mortality risk, possibly via enhanced atherosclerosis, vascular stiffness, and vascular calcification. The aim of this study was to examine the hypothesis that soluble Klotho and FGF23 exert direct, rapid effects on the vessel wall. We used three in vitro models: mouse aorta rings, human umbilical vein endothelial cells, and human vascular smooth muscle cells (HVSMC). Increasing medium concentrations of soluble Klotho and FGF23 both stimulated aorta contractions and increased ROS production in HVSMC. Klotho partially reverted FGF23 induced vasoconstriction, induced relaxation on phosphate preconstricted aorta and enhanced endothelial NO production in HUVEC. Thus Klotho increased both ROS production in HVSMC and NO production in endothelium. FGF23 induced contraction in phosphate preconstricted vessels and increased ROS production. Phosphate, Klotho and FGF23 together induced no change in vascular tone despite increased ROS production. Moreover, the three compounds combined inhibited relaxation despite increased NO production, probably owing to the concomitant increase in ROS production. In conclusion, although phosphate, soluble Klotho and FGF23 separately stimulate aorta contraction, Klotho mitigates the effects of phosphate and FGF23 on contractility via increased NO production, thereby protecting the vessel to some extent against potentially noxious effects of high phosphate or FGF23 concentrations. This novel observation is in line with the theory that Klotho deficiency is deleterious whereas Klotho sufficiency is protective against the negative effects of phosphate and FGF23 which are additive.
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Affiliation(s)
- Isabelle Six
- INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France
| | - Hirokazu Okazaki
- INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France
| | - Priscilla Gross
- INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France
| | - Joanna Cagnard
- INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France
| | - Cédric Boudot
- INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France
| | - Julien Maizel
- INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France
- Amiens University Medical Center, Amiens, France
| | - Tilman B. Drueke
- INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France
| | - Ziad A. Massy
- INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France
- Amiens University Medical Center, Amiens, France
- * E-mail:
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