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Palupi-Baroto R, Hermawan K, Murni IK, Nurlita T, Prihastuti Y, Puspitawati I, Tandri CC, Ambarsari CG. Carotid intima-media thickness, fibroblast growth factor 23, and mineral bone disorder in children with chronic kidney disease. BMC Nephrol 2024; 25:369. [PMID: 39433982 PMCID: PMC11494757 DOI: 10.1186/s12882-024-03771-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 09/23/2024] [Indexed: 10/23/2024] Open
Abstract
BACKGROUND Carotid intima-media thickness (cIMT) is a measure of atherosclerotic vascular disease and a surrogate biomarker for cardiovascular risk in patients with chronic kidney disease (CKD). Mineral and bone disorders (MBD) are complications of CKD, contributing to vascular calcification and accelerated atherosclerosis. Increased fibroblast growth factor 23 (FGF23)-the earliest detectable serum abnormality associated with CKD-MBD-has been linked with cardiovascular disease in patients with CKD. This study aimed to identify factors and analyze the relationship associated with high cIMT, high FGF23, and poor MBD control in children with CKD. METHODS A cross-sectional study was conducted in Yogyakarta, Indonesia recruiting children with CKD. The correlations and factors between cIMT, FGF23, and MBD were explored. RESULTS We recruited 42 children aged 2-18 years old with CKD stages 2 to 5D. There were no significant correlations between cIMT and factors including advanced CKD, use of dialysis, body mass index, hypertension, anemia, MBD, FGF23 levels, and left ventricular mass index (LVMI). Patients with advanced CKD had poorly controlled anemia, hypertension, and higher LVMI. In multivariate analysis, CKD stages, hypertension stages, the presence of MBD, and LVMI were associated with FGF23 levels (p < 0.05). CONCLUSIONS FGF23 levels increased with CKD progression, and MBD was more prevalent in advanced kidney disease. Elevated FGF23 is potentially associated with increased MBD prevalence in late-stage CKD. A larger study is needed to confirm the factors affecting cIMT in children with CKD.
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Affiliation(s)
- Retno Palupi-Baroto
- Division of Nephrology, Department of Child Health, Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada - Dr Sardjito Hospital, Jl. Farmako Sekip Utara, Yogyakarta, 55281, Indonesia.
| | - Kristia Hermawan
- Division of Nephrology, Department of Child Health, Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada - Dr Sardjito Hospital, Jl. Farmako Sekip Utara, Yogyakarta, 55281, Indonesia
| | - Indah Kartika Murni
- Division of Cardiology, Department of Child Health, Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada - Dr Sardjito Hospital, Yogyakarta, Indonesia
| | - Tiara Nurlita
- Department of Child Health, Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Yuli Prihastuti
- Department of Child Health, Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Ira Puspitawati
- Clinical Pathology and Laboratorium Medicine, Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada - Dr Sardjito Hospital, Yogyakarta, Indonesia
| | - Chika Carnation Tandri
- Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Cahyani Gita Ambarsari
- Department of Child Health, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo Hospital, Jakarta, Indonesia
- School of Medicine, University of Nottingham, Nottingham, UK
- Medical Technology Cluster, Indonesian Medical Education and Research Institute (IMERI), Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
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Lalayiannis AD, Soeiro EMD, Moysés RMA, Shroff R. Chronic kidney disease mineral bone disorder in childhood and young adulthood: a 'growing' understanding. Pediatr Nephrol 2024; 39:723-739. [PMID: 37624528 PMCID: PMC10817832 DOI: 10.1007/s00467-023-06109-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 07/06/2023] [Accepted: 07/19/2023] [Indexed: 08/26/2023]
Abstract
Chronic kidney disease (CKD) mineral and bone disorder (MBD) comprises a triad of biochemical abnormalities (of calcium, phosphate, parathyroid hormone and vitamin D), bone abnormalities (turnover, mineralization and growth) and extra-skeletal calcification. Mineral dysregulation leads to bone demineralization causing bone pain and an increased fracture risk compared to healthy peers. Vascular calcification, with hydroxyapatite deposition in the vessel wall, is a part of the CKD-MBD spectrum and, in turn, leads to vascular stiffness, left ventricular hypertrophy and a very high cardiovascular mortality risk. While the growing bone requires calcium, excess calcium can deposit in the vessels, such that the intake of calcium, calcium- containing medications and high calcium dialysate need to be carefully regulated. Normal physiological bone mineralization continues into the third decade of life, many years beyond the rapid growth in childhood and adolescence, implying that skeletal calcium requirements are much higher in younger people compared to the elderly. Much of the research into the link between bone (de)mineralization and vascular calcification in CKD has been performed in older adults and these data must not be extrapolated to children or younger adults. In this article, we explore the physiological changes in bone turnover and mineralization in children and young adults, the pathophysiology of mineral bone disease in CKD and a potential link between bone demineralization and vascular calcification.
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Affiliation(s)
- Alexander D Lalayiannis
- Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
- University College London Great Ormond Street Hospital Institute of Child Health, London, UK.
| | | | - Rosa M A Moysés
- Sao Paulo University Faculty of Medicine, Universidade de Sao Paulo Faculdade de Medicina, São Paulo, Brazil
| | - Rukshana Shroff
- University College London Great Ormond Street Hospital Institute of Child Health, London, UK
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3
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Liu D, Yang F, Zhang S, Guo Z, Peng S. Significance of changes in FGF23 levels in childhood primary nephrotic syndrome and children who progress to end‑stage renal disease. Exp Ther Med 2023; 26:390. [PMID: 37456167 PMCID: PMC10347369 DOI: 10.3892/etm.2023.12089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 06/01/2023] [Indexed: 07/18/2023] Open
Abstract
Fibroblast growth factor 23 (FGF23) is an important phosphaturic hormone, yet few studies have focused on FGF23 in children with primary nephrotic syndrome (PNS) and children who progressed to end-stage renal disease (ESRD). This cross-sectional study investigated the significance of changes in FGF23 levels in childhood PNS and children who progressed to ESRD. Of the 41 children included in the study, 17 had PNS with proteinuria and normal renal function (PNS group), 4 had ESRD (ESRD group), and 20 were healthy (control group). Following corticosteroid treatment, patients with PNS and proteinuria entered the remission phase. Serum levels of FGF23, phosphate, parathyroid hormone (PTH), 25-hydroxyvitamin D (25-OH-D), and calcium were measured. It was found that FGF23 levels in the PNS and ESRD groups were higher than those in the control group, while serum 25-OH-D levels were lower. Serum PTH levels increased significantly in the ESRD group. In the control group, FGF23 levels were negatively correlated with serum PTH and positively correlated with serum 25-OH-D. FGF23 levels were positively correlated with serum calcium and corrected calcium levels in children with PNS during the remission phase. Increased FGF23 levels in children with PNS, particularly in children who progressed to ESRD. It was also confirmed that serum FGF23 levels begin to rise in children with PNS prior to Stage 1 chronic kidney disease. These findings indicated that increased FGF23 levels may be associated with the progression and severity of nephrosis in children, and that serum FGF23 levels were useful for early detection of abnormal mineral metabolism in children with PNS.
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Affiliation(s)
- Ding Liu
- Department of Pediatrics, First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Fang Yang
- Department of Pediatrics, First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Sui Zhang
- Department of Pediatrics, First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Zhiqiang Guo
- Department of Pediatrics, First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Shuting Peng
- Department of Pediatrics, First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
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董 沙, 车 若, 郑 必, 张 爱, 王 春, 白 咪, 陈 颖. [Value of serum fibroblast growth factor 23 in diagnosis of hypophosphatemic rickets in children]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2023; 25:705-710. [PMID: 37529952 PMCID: PMC10414175 DOI: 10.7499/j.issn.1008-8830.2303016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 06/02/2023] [Indexed: 08/03/2023]
Abstract
OBJECTIVES To study the value of serum fibroblast growth factor 23 (FGF23) in the diagnosis of hypophosphatemic rickets in children. METHODS A total of 28 children who were diagnosed with hypophosphatemic rickets in Children's Hospital of Nanjing Medical University from January 2016 to June 2021 were included as the rickets group. Forty healthy children, matched for sex and age, who attended the Department of Child Healthcare of the hospital were included as the healthy control group. The serum level of FGF23 was compared between the two groups, and the correlations of the serum FGF23 level with clinical characteristics and laboratory test results were analyzed. The value of serum FGF23 in the diagnosis of hypophosphatemic rickets was assessed. RESULTS The rickets group had a significantly higher serum level of FGF23 than the healthy control group (P<0.05). In the rickets group, the serum FGF23 level was positively correlated with the serum alkaline phosphatase level (rs=0.38, P<0.05) and was negatively correlated with maximum renal tubular phosphorus uptake/glomerular filtration rate (rs=-0.64, P<0.05), while it was not correlated with age, height Z-score, sex, and parathyroid hormone (P>0.05). Serum FGF23 had a sensitivity of 0.821, a specificity of 0.925, an optimal cut-off value of 55.77 pg/mL, and an area under the curve of 0.874 in the diagnosis of hypophosphatemic rickets (P<0.05). CONCLUSIONS Serum FGF23 is of valuable in the diagnosis of hypophosphatemic rickets in children, which providing a theoretical basis for early diagnosis of this disease in clinical practice.
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Affiliation(s)
| | | | - 必霞 郑
- 南京医科大学附属儿童医院儿科学重点实验室,江苏南京210000
| | | | - 春莉 王
- 南京医科大学附属儿童医院儿科学重点实验室,江苏南京210000
| | - 咪 白
- 南京医科大学附属儿童医院儿科学重点实验室,江苏南京210000
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Pons-Belda OD, Alonso-Álvarez MA, González-Rodríguez JD, Mantecón-Fernández L, Santos-Rodríguez F. Mineral Metabolism in Children: Interrelation between Vitamin D and FGF23. Int J Mol Sci 2023; 24:ijms24076661. [PMID: 37047636 PMCID: PMC10094813 DOI: 10.3390/ijms24076661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 03/29/2023] [Accepted: 04/01/2023] [Indexed: 04/05/2023] Open
Abstract
Fibroblast growth factor 23 (FGF23) was identified at the turn of the century as the long-sought circulating phosphatonin in human pathology. Since then, several clinical and experimental studies have investigated the metabolism of FGF23 and revealed its relevant pathogenic role in various diseases. Most of these studies have been performed in adult individuals. However, the mineral metabolism of the child is, to a large extent, different from that of the adult because, in addition to bone remodeling, the child undergoes a specific process of endochondral ossification responsible for adequate mineralization of long bones’ metaphysis and growth in height. Vitamin D metabolism is known to be deeply involved in these processes. FGF23 might have an influence on bones’ growth as well as on the high and age-dependent serum phosphate concentrations found in infancy and childhood. However, the interaction between FGF23 and vitamin D in children is largely unknown. Thus, this review focuses on the following aspects of FGF23 metabolism in the pediatric age: circulating concentrations’ reference values, as well as those of other major variables involved in mineral homeostasis, and the relationship with vitamin D metabolism in the neonatal period, in vitamin D deficiency, in chronic kidney disease (CKD) and in hypophosphatemic disorders.
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Affiliation(s)
| | | | | | | | - Fernando Santos-Rodríguez
- Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
- Department of Medicine, Faculty of Medicine, University of Oviedo, 33003 Oviedo, Spain
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Kubota M, Hamasaki Y, Hashimoto J, Aoki Y, Kawamura T, Saito A, Yuasa R, Muramatsu M, Komaba H, Toyoda M, Fukagawa M, Shishido S, Sakai K. Fibroblast growth factor 23-Klotho and mineral metabolism in the first year after pediatric kidney transplantation: A single-center prospective study. Pediatr Transplant 2023; 27:e14440. [PMID: 36471536 DOI: 10.1111/petr.14440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 10/27/2022] [Accepted: 10/28/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND The role of fibroblast growth factor 23 (FGF23) levels in mineral metabolism before and after kidney transplantation in pediatric patients is poorly understood. METHODS We prospectively evaluated 24 patients under 18 years of age (4.5 [3.3-9.8] years) who underwent living kidney transplantation between July 2016 and March 2018, and measured intact FGF23 and serum αKlotho levels, and other parameters of mineral metabolism before and after transplantation (Day 7, 1 and 4 months, and 1 year). Relationships between parameters were examined by linear analysis. RESULTS FGF23 level was 440.8 [63.4-5916.3] pg/ml pre-transplant and decreased significantly to 37.1 [16.0-71.5] pg/ml at Day 7 post-transplant (-91.6%, p < .001). Thereafter, it remained at normal levels until 1 year. αKlotho level was 785 [568-1292] pg/ml pre-transplant and remained low at Day 7 and 1 month post-transplant, with an increasing trend at 4 months. Post-transplant phosphorus levels were significantly decreased compared with pre-transplant, with a lowest level of 1.7 [1.3-2.9] mg/dl, -5.7 [-6.8, -3.8] SD at Day 4, followed by gradual recovery. Phosphorus levels and the ratio of tubular maximum phosphate reabsorption were significantly and negatively associated with pre-transplant FGF23 until 4 months of post-transplant. Pre-transplant αKlotho was negatively associated with pre-transplant FGF23 but not FGF23 or other parameters after transplantation. CONCLUSION FGF23 in pediatric kidney transplant patients decreased rapidly after transplantation and associated with post-transplant hypophosphatemia and increased phosphorus excretion. Post-transplant αKlotho was low early post-transplant but tended to increase subsequently. Post-transplant αKlotho was unaffected by pre-transplant FGF23 or other factors, suggesting pre-transplant chronic kidney disease status has no effect.
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Affiliation(s)
- Mai Kubota
- Department of Nephrology, Toho University, Faculty of Medicine, Tokyo, Japan
| | - Yuko Hamasaki
- Department of Nephrology, Toho University, Faculty of Medicine, Tokyo, Japan
| | - Junya Hashimoto
- Department of Nephrology, Toho University, Faculty of Medicine, Tokyo, Japan
| | - Yujiro Aoki
- Department of Nephrology, Toho University, Faculty of Medicine, Tokyo, Japan
| | - Takeshi Kawamura
- Department of Nephrology, Toho University, Faculty of Medicine, Tokyo, Japan
| | - Akinobu Saito
- Department of Nephrology, Toho University, Faculty of Medicine, Tokyo, Japan
| | - Rena Yuasa
- Department of Nephrology, Toho University, Faculty of Medicine, Tokyo, Japan
| | - Masaki Muramatsu
- Department of Nephrology, Toho University, Faculty of Medicine, Tokyo, Japan
| | - Hirotaka Komaba
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan
| | - Masao Toyoda
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan
| | - Masafumi Fukagawa
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara, Japan
| | - Seichiro Shishido
- Department of Pediatric Nephrology, Toho University, Faculty of Medicine, Tokyo, Japan
| | - Ken Sakai
- Department of Nephrology, Toho University, Faculty of Medicine, Tokyo, Japan
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Jung J, Lee KH, Park E, Park YS, Kang HG, Ahn YH, Ha IS, Kim SH, Cho H, Han KH, Cho MH, Choi HJ, Lee JH, Shin JI. Mineral bone disorder in children with chronic kidney disease: Data from the KNOW-Ped CKD (Korean cohort study for outcome in patients with pediatric chronic kidney disease) study. Front Pediatr 2023; 11:994979. [PMID: 36873652 PMCID: PMC9982157 DOI: 10.3389/fped.2023.994979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 01/24/2023] [Indexed: 02/19/2023] Open
Abstract
BACKGROUND Children with chronic kidney disease (CKD) are at high risk of mineral bone disorder (MBD), which leads to fractures, growth retardation, and cardiovascular disease. We aimed to comprehensively understand the relationship between renal function and factors related to MBD and evaluate the prevalence and distribution characteristics of MBD, specifically among Korean patients from the KNOW-PedCKD cohort. METHODS From the baseline data of the KNOW-PedCKD cohort, we examined the prevalence and distribution of MBD in 431 Korean pediatric CKD patients, including the level of corrected total calcium, serum phosphate, serum alkaline phosphatase, serum intact parathyroid hormone (iPTH), fibroblast growth factor 23 (FGF-23), serum vitamin D, fractional excretion of phosphate (FEP), and bone densitometry Z-scores. RESULTS The median serum calcium level remained relatively normal regardless of the CKD stage. The levels of 1,25-dihydroxy vitamin D, urine calcium-to-creatinine ratio, and bone densitometry Z-score significantly decreased with advancing CKD stage, while those of serum phosphate, FGF-23, and FEP significantly increased with CKD stage. The prevalence of hyperphosphatemia (17.4%, 23.7%, and 41.2% from CKD stages 3b, 4, and 5, respectively) and hyperparathyroidism (37.3%, 57.4%, 55.3%, and 52.9% from CKD stages 3a, 3b, 4, and 5, respectively) significantly increased with the CKD stage. Prescriptions of medications, such as calcium supplements (39.1%, 42.1%, 82.4%), phosphate binders (39.1%, 43.4%, 82.4%), and active vitamin D (21.7%, 44.7%, and 64.7%) significantly increased with CKD stage 3b, 4, and 5, respectively. CONCLUSIONS The results demonstrated the prevalence and relationship of abnormal mineral metabolism and bone growth according to CKD stage in Korean pediatric CKD patients for the first time.
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Affiliation(s)
- Jiwon Jung
- Department of Pediatrics, Asan Medical Center Children's Hospital, Ulsan University, College of Medicine, Seoul, Republic of Korea
| | - Keum Hwa Lee
- Department of Pediatrics, Severance Children's Hospital, College of Medicine, University of Yonsei, Seoul, Republic of Korea
| | - Eujin Park
- Department of Pediatrics, Hallym University Kangnam Sacred Heart Hospital, Seoul, Republic of Korea
| | - Young Seo Park
- Department of Pediatrics, Asan Medical Center Children's Hospital, Ulsan University, College of Medicine, Seoul, Republic of Korea
| | - Hee Gyung Kang
- Department of Pediatrics, Seoul National University Children's Hospital, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Yo Han Ahn
- Department of Pediatrics, Seoul National University Children's Hospital, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Il-Soo Ha
- Department of Pediatrics, Seoul National University Children's Hospital, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Seong Heon Kim
- Department of Pediatrics, Seoul National University Children's Hospital, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Heeyeon Cho
- Department of Pediatrics, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Republic of Korea
| | - Kyoung Hee Han
- Department of Pediatrics, School of Medicine, Jeju National University, Jeju, Republic of Korea
| | - Min Hyun Cho
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Hyun Jin Choi
- National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Cheongju, Republic of Korea
| | - Joo Hoon Lee
- Department of Pediatrics, Asan Medical Center Children's Hospital, Ulsan University, College of Medicine, Seoul, Republic of Korea
| | - Jae Il Shin
- Department of Pediatrics, Severance Children's Hospital, College of Medicine, University of Yonsei, Seoul, Republic of Korea.,Institute of Kidney Disease Research, College of Medicine, Yonsei University, Seoul, Republic of Korea
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Ferraro S, Biganzoli G, Calcaterra V, Zuccotti G, Biganzoli EM, Plebani M. Fibroblast growth factor 23: translating analytical improvement into clinical effectiveness for tertiary prevention in chronic kidney disease. Clin Chem Lab Med 2022; 60:1694-1705. [PMID: 36008874 DOI: 10.1515/cclm-2022-0635] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 07/22/2022] [Indexed: 12/15/2022]
Abstract
OBJECTIVES Fibroblast growth factor 23 (FGF23) plays a key role in the pathophysiology of chronic kidney disease (CKD) and of the associated cardiovascular diseases, ranking on the crossroads of several evolving areas with a relevant impact on the health-care system (ageing, treatment of CKD and prevention from cardiovascular and renal events). In this review, we will critically appraise the overall issues concerning the clinical usefulness of FGF23 determination in CKD, focusing on the analytical performances of the methods, aiming to assess whether and how the clinical introduction of FGF23 may promote cost-effective health care policies in these patients. CONTENT Our comprehensive critical appraisal of the literature revealed that we are currently unable to establish the clinical usefulness of FGF23 measured by ELISA in CKD, as stability issues and suboptimal analytical performances are the major responsible for the release of misleading results. The meta-analytical approach has failed to report unambiguous evidence in face of the wide heterogeneity of the results from single studies. SUMMARY AND OUTLOOK Our review has largely demonstrated that the clinical usefulness depends on a thorough analytical validation of the assay. The recent introduction of chemiluminescent intact-FGF23 (iFGF23) assays licensed for clinical use, after passing a robust analytical validation, has allowed the actual assessment of preliminary risk thresholds for cardiovascular and renal events and is promising to capture the iFGF23 clinically relevant changes as a result of a therapeutic modulation. In this perspective, the analytical optimization of FGF23 determination may allow a marriage between physiology and epidemiology and a merging towards clinical outcomes.
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Affiliation(s)
- Simona Ferraro
- Endocrinology Laboratory Unit, "Luigi Sacco" University Hospital, Milan, Italy
| | - Giacomo Biganzoli
- Medical Statistics Unit, Department of Biomedical and Clinical Sciences L. Sacco, "Luigi Sacco" University Hospital, University of Milan, Milan, Italy
| | - Valeria Calcaterra
- Department of Internal Medicine, University of Pavia, Pavia, Italy.,Pediatric Department, "V. Buzzi" Children's Hospital, Milan, Italy
| | - Gianvincenzo Zuccotti
- Pediatric Department, "V. Buzzi" Children's Hospital, Milan, Italy.,Department of Biomedical and Clinical Science, University of Milan, Milan, Italy
| | - Elia Mario Biganzoli
- Medical Statistics Unit, Department of Biomedical and Clinical Sciences L. Sacco, "Luigi Sacco" University Hospital, University of Milan, Milan, Italy
| | - Mario Plebani
- Department of Medicine-DIMED, University of Padova, Padova, Italy
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9
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Miyakawa H, Hsu HH, Ogawa M, Akabane R, Miyagawa Y, Takemura N. Serum fibroblast growth factor-23 concentrations in young and mature adult cats with chronic kidney disease. J Feline Med Surg 2022; 24:815-820. [PMID: 34431737 PMCID: PMC10812289 DOI: 10.1177/1098612x211039192] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVES The aim of this study was to investigate serum fibroblast growth factor (FGF)-23 concentrations in young and mature adult cats with chronic kidney disease (CKD). METHODS The present study retrospectively investigated the serum samples and medical records of 1-8-year-old clinically healthy cats (control group, n = 7) and cats with CKD (n = 54). Cats with CKD were divided into four stages based on serum creatinine concentrations, according to the International Renal Interest Society (IRIS) CKD guidelines. Serum FGF-23 concentrations were compared between cats in the control group, IRIS stages 1, 2 and 3-4 CKD. Continuous variables were analysed using correlations and multiple linear regression. RESULTS Serum FGF-23 concentrations were significantly higher in cats with IRIS stages 1, 2 and 3-4 CKD, compared with those in the control group (P = 0.02, P = 0.002 and P = 0.002, respectively). Additionally, serum FGF-23 concentrations in cats with IRIS stages 3-4 CKD had higher serum FGF-23 concentrations than those with IRIS stages 1 and 2 CKD (P = 0.04 and P = 0.02, respectively). In the multiple linear regression analysis, serum urea nitrogen concentration, serum phosphorus concentration and blood ionised calcium concentration were independent variables predicting serum FGF-23 concentration. CONCLUSIONS AND RELEVANCE Serum FGF-23 concentrations in younger cats with CKD increased in early-stage CKD and were associated with mineral metabolic markers, as also occurs in geriatric cats.
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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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10
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Sirimongkolchaiyakul O, Wesseling‐Perry K, Gales B, Markovic D, Elashoff D, Ramos G, Pereira RC, Hanudel MR, Salusky IB. Effects of primary kidney disease etiology on renal osteodystrophy in pediatric dialysis patients. JBMR Plus 2022; 6:e10601. [PMID: 35434448 PMCID: PMC9009101 DOI: 10.1002/jbm4.10601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 01/11/2022] [Indexed: 11/06/2022] Open
Abstract
Congenital diseases of the kidney and urinary tract (CAKUT) and glomerulonephritis are the main causes of chronic kidney disease (CKD) in children. Although renal osteodystrophy (ROD) and indices of mineral metabolism have been characterized in dialyzed children, the impact of primary kidney disease on ROD is unknown. We performed a cross‐sectional study of bone biopsies performed in 189 pediatric dialysis patients aged 12.6 ± 5.4 years. Patients were classified into three groups according to primary kidney disease: CAKUT (n = 82), hereditary (n = 22), or glomerular disease (n = 85). Serum concentrations of calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and 25(OH) vitamin D were measured at the time of biopsy. Fibroblast growth factor 23 (FGF23) levels were measured in a subset of 59 patients. Levels of calcium, phosphate, PTH, and 25(OH) vitamin D were similar across groups. CAKUT patients had higher serum ALP and lower C‐terminal FGF23 levels. Bone turnover and bone volume parameters did not differ across groups. However, osteoid volume (OV/BV), osteoid surface (OS/BS), and osteoid maturation time (OMT) were highest in the CAKUT group and lowest in the hereditary group. Multiple regression analysis revealed that calcium, phosphate, ALP, and PTH were independently associated with OV/BV and osteoid thickness (O.Th). PTH was an independent factor affecting bone formation rate. The relationship between CKD etiology and bone histomorphometric variables was abrogated after adjustment for biochemical parameters in the multivariable models. Overall, bone histology differed according to CKD etiology in the unadjusted analysis; however, this association could not be confirmed independently of biochemical parameters. Although CAKUT patients had a greater mineralization defect with elevated serum ALP levels, longitudinal studies will be needed to elucidate mediation pathways that might be involved in the complex interplay of CKD‐mineral bone disease (MBD). © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Ornatcha Sirimongkolchaiyakul
- Department of Pediatrics David Geffen School of Medicine at the University of California Los Angeles United States
- Department of Pediatrics, Faculty of Medicine Vajira Hospital Navamindrahiraj University Bangkok Thailand
| | - Katherine Wesseling‐Perry
- Department of Pediatrics David Geffen School of Medicine at the University of California Los Angeles United States
| | - Barbara Gales
- Department of Pediatrics David Geffen School of Medicine at the University of California Los Angeles United States
| | - Daniela Markovic
- Department of Medicine, Biostatistics and Biomathematics David Geffen School of Medicine at the University of California Los Angeles United States
| | - David Elashoff
- Department of Medicine, Biostatistics and Biomathematics David Geffen School of Medicine at the University of California Los Angeles United States
| | - Georgina Ramos
- Department of Pediatrics David Geffen School of Medicine at the University of California Los Angeles United States
| | - Renata C. Pereira
- Department of Pediatrics David Geffen School of Medicine at the University of California Los Angeles United States
| | - Mark R. Hanudel
- Department of Pediatrics David Geffen School of Medicine at the University of California Los Angeles United States
| | - Isidro B. Salusky
- Department of Pediatrics David Geffen School of Medicine at the University of California Los Angeles United States
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11
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Abstract
PURPOSE OF REVIEW Fibroblast growth factor 23 (FGF23) is a bone- and bone marrow-derived hormone that is critical to maintain phosphate homeostasis. The principal actions of FGF23 are to reduce serum phosphate levels by decreasing kidney phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis. FGF23 deficiency causes hyperphosphatemia and ectopic calcifications, while FGF23 excess causes hypophosphatemia and skeletal defects. Excess FGF23 also correlates with kidney disease, where it is associated with increased morbidity and mortality. Accordingly, FGF23 levels are tightly regulated, but the mechanisms remain incompletely understood. RECENT FINDINGS In addition to bone mineral factors, additional factors including iron, erythropoietin, inflammation, energy, and metabolism regulate FGF23. All these factors affect Fgf23 expression, while some also regulate FGF23 protein cleavage. Conversely, FGF23 may have a functional role in regulating these biologic processes. Understanding the bi-directional relationship between FGF23 and non-bone mineral factors is providing new insights into FGF23 regulation and function.
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Affiliation(s)
- Petra Simic
- Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
| | - Jodie L Babitt
- Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Program in Membrane Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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12
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Stanczyk M, Chrul S, Wyka K, Tkaczyk M. Serum intact fibroblast growth factor 23 in healthy paediatric population. Open Med (Wars) 2021; 16:1022-1027. [PMID: 34258392 PMCID: PMC8262519 DOI: 10.1515/med-2021-0288] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 03/28/2021] [Accepted: 04/20/2021] [Indexed: 11/25/2022] Open
Abstract
Introduction It is believed that fibroblast growth factor 23 (FGF23) can become an early biomarker of chronic kidney disease progression. Data on FGF23 age dependency are inconsistent. We present the results of the cross-sectional study concerning FGF23 levels in healthy Polish children. Material and methods This study was conducted in 121 children aged 0–18 years. Kidney function and intact FGF23 levels in serum were assessed. Differences between age groups and according to gender were analysed. Results The difference in FGF23 between age groups and according to gender was statistically insignificant. In the youngest and the oldest group, a trend to higher FGF23 levels was observed. FGF23 level in girls tended to be higher than boys, apart from the age group between 1 and 4 years. There was a negative correlation between eGFR and FGF23 (r = −0.26, p < 0.05) – strong in girls (r = −0.38, p < 0.05), but not in boys. In each age group, we found no significant correlation between eGFR and FGF23. Conclusions Our study supports the evidence that the FGF23 level in paediatric population is not age or sex dependent. The results can serve as a reference point under clinical conditions and for other studies on the topic.
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Affiliation(s)
- Malgorzata Stanczyk
- Department of Pediatrics, Immunology and Nephrology, Polish Mother's Memorial Hospital Research Institute, Rzgowska 281/289, Lodz 93-338, Poland.,Department of Pediatrics, Preventive Cardiology and Immunology of Developmental Age, Medical University of Lodz, Poland
| | - Slawomir Chrul
- Department of Pediatrics, Immunology and Nephrology, Polish Mother's Memorial Hospital Research Institute, Lodz 93-338, Poland
| | - Krystyna Wyka
- Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, Lodz, Poland
| | - Marcin Tkaczyk
- Department of Pediatrics, Immunology and Nephrology, Polish Mother's Memorial Hospital Research Institute, Lodz 93-338, Poland.,Department of Pediatrics, Preventive Cardiology and Immunology of Developmental Age, Medical University of Lodz, Poland
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13
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FGF23: A Review of Its Role in Mineral Metabolism and Renal and Cardiovascular Disease. DISEASE MARKERS 2021; 2021:8821292. [PMID: 34055103 PMCID: PMC8149241 DOI: 10.1155/2021/8821292] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 11/01/2020] [Accepted: 05/04/2021] [Indexed: 01/03/2023]
Abstract
FGF23 is a hormone secreted mainly by osteocytes and osteoblasts in bone. Its pivotal role concerns the maintenance of mineral ion homeostasis. It has been confirmed that phosphate and vitamin D metabolisms are related to the effect of FGF23 and its excess or deficiency leads to various hereditary diseases. Multiple studies have shown that FGF23 level increases in the very early stages of chronic kidney disease (CKD), and its concentration may also be highly associated with cardiac complications. The present review is limited to some of the most important aspects of calcium and phosphate metabolism. It discusses the role of FGF23, which is considered an early and sensitive marker for CKD-related bone disease but also as a novel and potent cardiovascular risk factor. Furthermore, this review gives particular attention to the reliability of FGF23 measurement and various confounding factors that may impact on the clinical utility of FGF23. Finally, this review elaborates on the clinical usefulness of FGF23 and evaluates whether FGF23 may be considered a therapeutic target.
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14
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Santos F, Díaz-Anadón L, Ordóñez FA, Haffner D. Bone Disease in CKD in Children. Calcif Tissue Int 2021; 108:423-438. [PMID: 33452890 DOI: 10.1007/s00223-020-00787-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 12/04/2020] [Indexed: 01/03/2023]
Abstract
This manuscript discusses mineral and bone disorders of chronic kidney disease (MBD-CKD) in pediatric patients with special emphasis on the underlying pathophysiology, the causes and clinical profile of growth retardation, the alterations in the growth plate, the strategies to optimize growth and the medical recommendations for prevention and treatment.
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Affiliation(s)
- Fernando Santos
- Division of Pediatric Nephrology, Hospital, Universitario Central de Asturias, Avda de Roma s/n, 33011, Oviedo, Asturias, Spain.
- Department of Medicine, University of Oviedo, Oviedo, Asturias, Spain.
| | - Lucas Díaz-Anadón
- Division of Pediatric Nephrology, Hospital, Universitario Central de Asturias, Avda de Roma s/n, 33011, Oviedo, Asturias, Spain
| | - Flor A Ordóñez
- Division of Pediatric Nephrology, Hospital, Universitario Central de Asturias, Avda de Roma s/n, 33011, Oviedo, Asturias, Spain
| | - Dieter Haffner
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
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15
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Satomura Y, Bessho K, Kitaoka T, Takeyari S, Ohata Y, Kubota T, Ozono K. Neonatal cholestasis can be the first symptom of McCune–Albright syndrome: A case report. World J Clin Pediatr 2021; 10:7-14. [PMID: 33758748 PMCID: PMC7958557 DOI: 10.5409/wjcp.v10.i2.7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/22/2021] [Accepted: 02/12/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND McCune–Albright syndrome (MAS) is caused by postzygotic somatic mutations of the GNAS gene. It is characterized by the clinical triad of fibrous dysplasia, café-au-lait skin spots, and endocrinological dysfunction. Myriad complications in MAS, including hepatobiliary manifestations, are also reported.
CASE SUMMARY This is a case of a 4-year-old boy who presented with MAS with neonatal cholestasis. He was suspected to have Alagille syndrome due to neonatal cholestasis with intrahepatic bile duct paucity in liver biopsy, peripheral pulmonary artery stenosis, and renal tubular dysfunction. By the age of 2 years, his cholestatic liver injury gradually improved, but he had repeated left femoral fractures. He did not exhibit endocrinological abnormality or café-au-lait skin spots. However, MAS was suspected due to fibrous dysplasia at the age of 4 years. No mutation was identified in the GNAS gene in the DNA isolated from the peripheral blood, but an activating point mutation (c.601C>T, p.Arg201Cys) was observed in the DNA extracted from the affected bone tissue and that extracted from the formalin-fixed paraffin-embedded liver tissue, which was obtained at the age of 1 mo.
CONCLUSION MAS should be considered as a differential diagnosis for transient cholestasis in infancy.
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Affiliation(s)
- Yoshinori Satomura
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Kazuhiko Bessho
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Taichi Kitaoka
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Shinji Takeyari
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Yasuhisa Ohata
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Takuo Kubota
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Keiichi Ozono
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
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16
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Bakkaloglu SA, Bacchetta J, Lalayiannis AD, Leifheit-Nestler M, Stabouli S, Haarhaus M, Reusz G, Groothoff J, Schmitt CP, Evenepoel P, Shroff R, Haffner D. Bone evaluation in paediatric chronic kidney disease: clinical practice points from the European Society for Paediatric Nephrology CKD-MBD and Dialysis working groups and CKD-MBD working group of the ERA-EDTA. Nephrol Dial Transplant 2021; 36:413-425. [PMID: 33245331 DOI: 10.1093/ndt/gfaa210] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Indexed: 11/13/2022] Open
Abstract
Mineral and bone disorder (MBD) is widely prevalent in children with chronic kidney disease (CKD) and is associated with significant morbidity. CKD may cause disturbances in bone remodelling/modelling, which are more pronounced in the growing skeleton, manifesting as short stature, bone pain and deformities, fractures, slipped epiphyses and ectopic calcifications. Although assessment of bone health is a key element in the clinical care of children with CKD, it remains a major challenge for physicians. On the one hand, bone biopsy with histomorphometry is the gold standard for assessing bone health, but it is expensive, invasive and requires expertise in the interpretation of bone histology. On the other hand, currently available non-invasive measures, including dual-energy X-ray absorptiometry and biomarkers of bone formation/resorption, are affected by growth and pubertal status and have limited sensitivity and specificity in predicting changes in bone turnover and mineralization. In the absence of high-quality evidence, there are wide variations in clinical practice in the diagnosis and management of CKD-MBD in childhood. We present clinical practice points (CPPs) on the assessment of bone disease in children with CKD Stages 2-5 and on dialysis based on the best available evidence and consensus of experts from the CKD-MBD and Dialysis working groups of the European Society for Paediatric Nephrology and the CKD-MBD working group of the European Renal Association-European Dialysis and Transplant Association. These CPPs should be carefully considered by treating physicians and adapted to individual patients' needs as appropriate. Further areas for research are suggested.
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Affiliation(s)
- Sevcan A Bakkaloglu
- Department of Paediatric Nephrology, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Justine Bacchetta
- Department of Paediatric Nephrology, Rheumatology and Dermatology, University Children's Hospital, Lyon, France
| | - Alexander D Lalayiannis
- Renal Unit, UCL Great Ormond Street Hospital for Children Institute of Child Health, London, UK
| | - Maren Leifheit-Nestler
- Department of Paediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children's Hospital, Hannover, Germany
| | - Stella Stabouli
- First Department of Paediatrics, Aristotle University Thessaloniki, Thessaloniki, Greece
| | - Mathias Haarhaus
- Division of Renal Medicine and Baxter Novum, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.,Diaverum AB, Stockholm, Sweden
| | - George Reusz
- First Department of Paediatrics, Semmelweis University, Budapest, Hungary
| | - Jaap Groothoff
- Department of Paediatric Nephrology, Emma Children's Hospital, Amsterdam, The Netherlands
| | - Claus Peter Schmitt
- Division of Paediatric Nephrology, Center for Paediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany
| | - Pieter Evenepoel
- Department of Microbiology and Immunology, Laboratory of Nephrology, KU Leuven, Leuven, Belgium.,Department of Nephrology, University Hospitals Leuven, Leuven, Belgium
| | - Rukshana Shroff
- Renal Unit, UCL Great Ormond Street Hospital for Children Institute of Child Health, London, UK
| | - Dieter Haffner
- Department of Paediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children's Hospital, Hannover, Germany
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17
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Karava V, Christoforidis A, Kondou A, Dotis J, Printza N. Update on the Crosstalk Between Adipose Tissue and Mineral Balance in General Population and Chronic Kidney Disease. Front Pediatr 2021; 9:696942. [PMID: 34422722 PMCID: PMC8378583 DOI: 10.3389/fped.2021.696942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Accepted: 07/06/2021] [Indexed: 11/17/2022] Open
Abstract
Adipose tissue is nowadays considered as a major endocrine organ, which apart from controlling lipid metabolism, displays a significant role in energy expenditure, food intake and in the regulation of various systemic physiological processes. Adipose derived pro-inflammatory cytokines and adipokines, particularly leptin and adiponectin, provide inter-communication of adipose tissue with various metabolic pathways, ultimately resulting in a complex network of interconnected organ systems. Recent clinical and experimental research has been focused on exploring the direct interaction between adipokine profile and elements of mineral metabolism, including parathormone (PTH), fibroblast growth factor-23 (FGF23) and calcitriol. The emerging crosstalk between adipose tissue and calcium and phosphorus homeostasis suggests that metabolic disorders from one system may directly affect the other and vice versa. It is current knowledge that fat metabolism disturbance, commonly encountered in obese individuals, influences the expression of calciotriopic hormones in general population, while various clinical trials attempting to successfully achieve body fat loss by modulating mineral profile have been published. In chronic kidney disease (CKD) state, there is an increasing evidence suggesting that mineral disorders, influence adipose tissue and linked endocrine function. On the contrary, the impact of disturbed fat metabolism on CKD related mineral disorders has been also evocated in clinical studies. Recognizing the pathogenetic mechanisms of communication between adipose tissue and mineral balance is critical for understanding the effects of metabolic perturbations from the one system to the other and for identifying possible therapeutic targets in case of disrupted homeostasis in one of the two connected systems. To that end, this review aims to enlighten the recent advances regarding the interplay between mineral metabolism, fat mass and adipokine profile, based on in vitro, in vivo and clinical studies, in general population and in the course of CKD.
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Affiliation(s)
- Vasiliki Karava
- Pediatric Nephrology Unit, 1st Department of Pediatrics, Hippokratio General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Athanasios Christoforidis
- Pediatric Endocrinology Unit, 1st Department of Pediatrics, Hippokratio General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Antonia Kondou
- Pediatric Nephrology Unit, 1st Department of Pediatrics, Hippokratio General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - John Dotis
- Pediatric Nephrology Unit, 1st Department of Pediatrics, Hippokratio General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Nikoleta Printza
- Pediatric Nephrology Unit, 1st Department of Pediatrics, Hippokratio General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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18
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Abstract
The Klotho proteins, αKlotho and βKlotho, are essential components of endocrine fibroblast growth factor (FGF) receptor complexes, as they are required for the high-affinity binding of FGF19, FGF21 and FGF23 to their cognate FGF receptors (FGFRs). Collectively, these proteins form a unique endocrine system that governs multiple metabolic processes in mammals. FGF19 is a satiety hormone that is secreted from the intestine on ingestion of food and binds the βKlotho-FGFR4 complex in hepatocytes to promote metabolic responses to feeding. By contrast, under fasting conditions, the liver secretes the starvation hormone FGF21, which induces metabolic responses to fasting and stress responses through the activation of the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system following binding to the βKlotho-FGFR1c complex in adipocytes and the suprachiasmatic nucleus, respectively. Finally, FGF23 is secreted by osteocytes in response to phosphate intake and binds to αKlotho-FGFR complexes, which are expressed most abundantly in renal tubules, to regulate mineral metabolism. Growing evidence suggests that the FGF-Klotho endocrine system also has a crucial role in the pathophysiology of ageing-related disorders, including diabetes, cancer, arteriosclerosis and chronic kidney disease. Therefore, targeting the FGF-Klotho endocrine axes might have therapeutic benefit in multiple systems; investigation of the crystal structures of FGF-Klotho-FGFR complexes is paving the way for the development of drugs that can regulate these axes.
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Affiliation(s)
- Makoto Kuro-O
- Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan. .,Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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19
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Bacchetta J, Ginhoux T, Bernoux D, Dubourg L, Ranchin B, Roger C. Assessment of mineral and bone biomarkers highlights a high frequency of hypercalciuria in asymptomatic healthy teenagers. Acta Paediatr 2019; 108:2253-2260. [PMID: 31215071 DOI: 10.1111/apa.14907] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 05/27/2019] [Accepted: 06/17/2019] [Indexed: 11/30/2022]
Abstract
AIM Assessment of mineral metabolism is complex in paediatrics. METHODS We assessed the evolution of the main mineral and bone biomarkers (total/bone alkaline phosphatase ALP/BAP, β-crosslaps, osteocalcin, sclerostin, C-terminal and intact FGF23) in 100 healthy teenagers (10-18 years, 50 boys). RESULTS At a mean age of 13.7 ± 2.2 years, phosphatemia, tubular phosphate reabsorption, ALP and BAP significantly decreased along puberty in both genders, whilst parathyroid hormone (PTH), 25-vitamin D (25D), FGF23, plasma calcium and urinary calcium were not modified. In girls, osteocalcin, β-crosslaps and sclerostin significantly decreased at the end of puberty. Calciuria above the crystallisation threshold (>3.8 mmol/L) and urinary calcium/creatinine ratio >0.7 mmol/mmol were found in 39% and 6% of subjects, respectively. Multivariable analyses showed that renal function and PTH were significant predictors of calciuria and urinary calcium/creatinine, whilst 25D remained a predictor only of urinary calcium/creatinine ratio. CONCLUSION Using the most recent assays, this study provides data for mineral/bone biomarkers across puberty and highlights the risk of hyper-calciuria in apparent asymptomatic healthy teenagers, not related to calcium intake but rather to 25D. Future studies are required to dissect the underlying mechanisms increasing calciuria and prevent nephrolithiasis as early as during childhood.
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Affiliation(s)
- Justine Bacchetta
- Centre de Référence des Maladies Rares du Calcium et du Phosphore Service de Néphrologie Rhumatologie et Dermatologie Pédiatriques Hôpital Femme Mère Enfant Bron France
- Faculté de Médecine Lyon Est Université Claude Bernard Lyon 1 Lyon France
- INSERM UMR 1033 Lyon France
| | - Tiphanie Ginhoux
- EPICIME‐CIC 1407 de Lyon, Inserm Service de Pharmacotoxicologie CHU‐Lyon Bron France
| | - Delphine Bernoux
- EPICIME‐CIC 1407 de Lyon, Inserm Service de Pharmacotoxicologie CHU‐Lyon Bron France
- Service d'Endocrinologie, Diabétologie et Métabolisme pédiatriques Hôpital Femme Mère Enfant Bron France
| | - Laurence Dubourg
- Faculté de Médecine Lyon Est Université Claude Bernard Lyon 1 Lyon France
- Néphrologie, Dialyse, Hypertension et Exploration Fonctionnelle Rénale Groupement Hospitalier Edouard Herriot Hospices Civils de Lyon Lyon France
- Laboratory of Tissue Biology and Therapeutic Engineering UMR 5305 CNRS University Lyon 1 Lyon France
| | - Bruno Ranchin
- Centre de Référence des Maladies Rares du Calcium et du Phosphore Service de Néphrologie Rhumatologie et Dermatologie Pédiatriques Hôpital Femme Mère Enfant Bron France
| | - Christelle Roger
- Laboratoire de Biochimie et Biologie Moléculaire Groupe Hospitalier Sud Hospices Civils de Lyon Lyon France
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20
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Delucchi Á, Toro L, Alzamora R, Barrientos V, González M, Andaur R, León P, Villanueva F, Galindo M, Las Heras F, Montecino M, Moena D, Lazcano A, Pinto V, Salas P, Reyes ML, Mericq V, Michea L. Glucocorticoids Decrease Longitudinal Bone Growth in Pediatric Kidney Transplant Recipients by Stimulating the FGF23/FGFR3 Signaling Pathway. J Bone Miner Res 2019; 34:1851-1861. [PMID: 31099911 DOI: 10.1002/jbmr.3761] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Revised: 05/05/2019] [Accepted: 05/11/2019] [Indexed: 12/11/2022]
Abstract
Renal transplantation (RTx) is an effective therapy to improve clinical outcomes in pediatric patients with terminal chronic kidney disease. However, chronic immunosuppression with glucocorticoids (GCs) reduces bone growth and BMD. The mechanisms causing GC-induced growth impairment have not been fully clarified. Fibroblast growth factor 23 (FGF23) is a peptide hormone that regulates phosphate homeostasis and bone growth. In pathological conditions, FGF23 excess or abnormal FGF receptors (FGFR) activity leads to bone growth impairment. Experimental data indicate that FGF23 expression is induced by chronic GC exposure. Therefore, we hypothesize that GCs impair bone growth by increasing FGF23 expression, which has direct effects on bone growth plate. In a post hoc analysis of a multicentric randomized clinical trial of prepubertal RTx children treated with early GC withdrawal or chronic GC treatment, we observed that GC withdrawal was associated with improvement in longitudinal growth and BMD, and lower plasma FGF23 levels as compared with a chronic GC group. In prepubertal rats, GC-induced bone growth retardation correlated with increased plasma FGF23 and bone FGF23 expression. Additionally, GC treatment decreased FGFR1 expression whereas it increased FGFR3 expression in mouse tibia explants. The GC-induced bone growth impairment in tibiae explants was prevented by blockade of FGF23 receptors using either a pan-FGFR antagonist (PD173074), a C-terminal FGF23 peptide (FGF23180-205) which blocks the binding of FGF23 to the FGFR-Klotho complex or a specific FGFR3 antagonist (P3). Finally, local administration of PD173074 into the tibia growth plate ameliorated cartilage growth impairment in GC-treated rats. These results show that GC treatment partially reduces longitudinal bone growth via upregulation of FGF23 and FGFR3 expression, thus suggesting that the FGF23/Klotho/FGFR3 axis at the growth plate could be a potential therapeutic target for the management of GC-induced growth impairment in children.
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Affiliation(s)
- Ángela Delucchi
- Division of Nephrology, Hospital Luis Calvo Mackenna, Santiago, Chile.,Division of Nephrology, Clínica Alemana de Santiago, Santiago, Chile
| | - Luis Toro
- Division of Nephrology, Department of Medicine, Hospital Clínico Universidad de Chile, Santiago, Chile.,Centro de Investigación Clínica Avanzada, Hospital Clínico Universidad de Chile, Santiago, Chile.,Clinica Las Condes, Santiago, Chile
| | - Rodrigo Alzamora
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago, Chile
| | - Victor Barrientos
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Magdalena González
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Rodrigo Andaur
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Pablo León
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Francisco Villanueva
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Mario Galindo
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy (MIII), Santiago, Chile
| | - Facundo Las Heras
- Clinica Las Condes, Santiago, Chile.,Department of Anatomic Pathology, Hospital Clínico Universidad de Chile, Santiago, Chile
| | - Martín Montecino
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andrés Bello, Santiago, Chile.,FONDAP Center for Genome Regulation, Universidad Andres Bello, Santiago, Chile
| | - Daniel Moena
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andrés Bello, Santiago, Chile.,FONDAP Center for Genome Regulation, Universidad Andres Bello, Santiago, Chile
| | - Andrea Lazcano
- Division of Nephrology, Clínica Alemana de Santiago, Santiago, Chile.,Division of Nephrology, Hospital de Niños Roberto del Río, Santiago, Chile
| | - Viola Pinto
- Clinica Las Condes, Santiago, Chile.,Pediatric Nephrology Unit, Hospital Doctor Exequiel González Cortés, Santiago, Chile
| | - Paulina Salas
- Pediatric Nephrology Unit, Hospital Doctor Exequiel González Cortés, Santiago, Chile
| | - María Loreto Reyes
- Pediatric Endocrinology Unit, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Verónica Mericq
- Clinica Las Condes, Santiago, Chile.,Institute of Maternal and Child Research, Universidad de Chile, Santiago, Chile
| | - Luis Michea
- Division of Nephrology, Department of Medicine, Hospital Clínico Universidad de Chile, Santiago, Chile.,Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Millennium Institute on Immunology and Immunotherapy (MIII), Santiago, Chile
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21
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Sargent HJ, Jepson RE, Chang YM, Biourge VC, Bijsmans ES, Elliott J. Fibroblast growth factor 23 and symmetric dimethylarginine concentrations in geriatric cats. J Vet Intern Med 2019; 33:2657-2664. [PMID: 31568615 PMCID: PMC6872607 DOI: 10.1111/jvim.15590] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 07/24/2019] [Indexed: 01/02/2023] Open
Abstract
Background Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that is increased in azotemic cats with chronic kidney disease (CKD) and predictive of the onset of azotemia in older cats. The introduction of symmetric dimethylarginine (SDMA) as a biomarker of glomerular filtration rate has led to the identification of cats in which SDMA is increased, but plasma creatinine concentrations remains within reference range. There is currently little understanding of the metabolic changes present in such cats. Objectives To examine the relationship between plasma FGF23 and SDMA concentrations in non‐azotemic geriatric cats. Animals Records of a cross section of client‐owned cats (n = 143) without azotemic CKD. Methods Clinicopathological information was obtained from cats (≥ 9 years) from records of 2 first opinion practices. The relationship between plasma SDMA and FGF23 concentrations was examined using Spearman's correlation and variables compared using the Mann‐Whitney U test. Results Cats with increased SDMA concentrations had significantly higher plasma FGF23 (P < .001) and creatinine (P < .001) concentrations compared to cats with SDMA concentrations within reference range. A weak positive relationship was demonstrated between plasma FGF23 and SDMA concentrations (r = .35, P < .001) and between plasma FGF23 and creatinine (r = .23, P = .005) concentrations. Conclusions and Clinical Importance More cats with increased SDMA concentrations had higher FGF23 concentrations than those with SDMA concentrations within the reference range, suggesting the presence of an alteration in phosphate homeostasis. Further studies are warranted to identify influencing factors and to explore the utility of FGF23 concentration to inform management of cats with early stage CKD.
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Affiliation(s)
- Hannah J Sargent
- Department of Comparative Biomedical Science, Royal Veterinary College, University of London, London, United Kingdom
| | - Rosanne E Jepson
- Department of Clinical Science and Services Royal Veterinary College, University of London, London, United Kingdom
| | - Yu-Mei Chang
- Research Support Office, Royal Veterinary College, University of London, London, United Kingdom
| | | | | | - Jonathan Elliott
- Department of Comparative Biomedical Science, Royal Veterinary College, University of London, London, United Kingdom
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Assessment of the Concentration of Bone Metabolism Markers: Sclerostin and FGF-23 in Children with Idiopathic Nephrotic Syndrome Treated with Glucocorticosteroids. DISEASE MARKERS 2019; 2019:9698367. [PMID: 31354894 PMCID: PMC6636590 DOI: 10.1155/2019/9698367] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 01/18/2019] [Accepted: 03/18/2019] [Indexed: 11/17/2022]
Abstract
Recurring nature of idiopathic nephrotic syndrome (INS) and steroid dependence imply a long-term treatment with glucocorticosteroids (GCSs), which increases the risk of bone metabolism disorders. The search for new markers of that process is essential. The aims of this study were to assess the concentrations of sclerostin (Scl) and fibroblast growth factor-23 (FGF-23) in the plasma of children with INS and compare Scl and FGF-23 to existing markers of bone metabolism, mainly parathyroid hormone (PTH). The study involved 70 children, 50 with INS and 20 healthy children. Patients with INS were divided into 4 groups depending on the number of relapses and applied therapy. Significantly higher concentrations of FGF-23 and Scl were found in all patient groups with INS compared to the control group, and increase in the concentrations of examined parameters depending on the number of NS relapses was showed. In patients from the group with numerous relapses, higher concentrations of FGF-23 and Scl in the relapse phase than those in the remission phase were found. We observed positive correlation in these proteins with parathyroid hormone. Positive correlation of FGF-23 and Scl in the examined group was noted. Children having relapsing INS treated with steroids have higher levels of Scl and FGF-23 that can indicate the bone metabolism disorders. The significance of these observations requires further research.
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23
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Benito S, Sánchez-Ortega A, Unceta N, Goicolea M, Barrio R. LC-QQQ-MS routine analysis method for new biomarker quantification in plasma aimed at early chronic kidney disease diagnosis. J Pharm Biomed Anal 2019; 169:82-89. [DOI: 10.1016/j.jpba.2019.02.042] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 02/25/2019] [Accepted: 02/26/2019] [Indexed: 12/28/2022]
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Pathogenesis and treatment of electrolyte problems post transplant. Curr Opin Pediatr 2019; 31:213-218. [PMID: 30585865 DOI: 10.1097/mop.0000000000000715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW Electrolyte abnormalities posttransplant are common occurrences that can have significant short-term and long-term effects on graft outcome and patient quality of life. Understanding the pathophysiology of these electrolyte derangements can help guide management to optimize bone health and minimize cardiovascular disease. This review explores the pathogenesis of the most common postrenal transplant electrolytes abnormalities as well as current treatment options. RECENT FINDINGS Clarifications of the role of FGF-23 has improved our understanding of posttransplant bone disease in addition to the known roles of hyperparathyroidism and vitamin D. The mechanisms of renal electrolyte wasting by immunosuppressive agents give insight into potential treatment options for hyperkalemia and hypomagnesemia. SUMMARY Understanding the pathogenesis of the common electrolyte abnormalities found post renal transplant may lead to targeted treatment options that in turn may improve transplant complications. Further studies are required to evaluate the effects on long-term outcomes of renal allografts.
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25
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Fauconnier C, Roy T, Gillerot G, Roy C, Pouleur AC, Gruson D. FGF23: Clinical usefulness and analytical evolution. Clin Biochem 2019; 66:1-12. [PMID: 30853324 DOI: 10.1016/j.clinbiochem.2019.03.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 02/05/2019] [Accepted: 03/05/2019] [Indexed: 12/16/2022]
Abstract
Fibroblast Growth Factor 23 (FGF23) is a key hormone for the regulation of phosphate homeostasis. Over the past decades, FGF23 was the subject of intense research in the fields of nephrology and the cardiology. It presents a remarkable correlation with well-established biomarkers of cardiovascular disorders in both chronic kidney disease (CKD) and heart failure (HF) patients. The interest of FGF23 lies in its early-onset in the primary course of CKD as well as in the incremental prognosis information it conveys in both CKD and HF. Different types of assays of FGF-23 testing exist, those targeting the intact form (iFGF23), the other one detecting terminal fragments (cFGF23). The issue is still pending which assay suits best for clinical use. Recently, the implementation of this biomarker on multianalyzer platforms, on which other markers of phospho-calcic balance are set up, allows a rapid turn-around-time and a potential financial gain. However, despite the good analytical performances of the automated methods, there is a poor harmonization between assays. The introduction of an international certified reference material should standardize the measurement and improve the harmonization of results from different laboratories. A deeper understanding of physio-pathological mechanisms and processing of FGF-23 should reinforce its clinical indications and might also identify new therapeutic targets for the treatment of CKD and HF.
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Affiliation(s)
- Charlotte Fauconnier
- Department of Laboratory Medicine, Cliniques Universitaires St-Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Tatiana Roy
- Department of Laboratory Medicine, Clinique Saint-Pierre Ottignies, Belgium
| | - Gaëlle Gillerot
- Nephrology Department, Clinique Saint-Pierre Ottignies, Belgium
| | - Clotilde Roy
- Division of Cardiology, Department of Cardiovascular Diseases, Cliniques Universitaires St. Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Anne-Catherine Pouleur
- Division of Cardiology, Department of Cardiovascular Diseases, Cliniques Universitaires St. Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Damien Gruson
- Department of Laboratory Medicine, Cliniques Universitaires St-Luc, Université Catholique de Louvain, Brussels, Belgium; Pôle de recherche en endocrinologie, diabète et nutrition, Institut de recherche expérimentale et clinique, Cliniques universitaires Saint-Luc et Université catholique de Louvain, Bruxelles, Belgium.
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26
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Lin Y, Shi L, Liu Y, Zhang H, Liu Y, Huang X, Hou D, Zhang M. Plasma Fibroblast Growth Factor 23 Is Elevated in Pediatric Primary Hypertension. Front Pediatr 2019; 7:135. [PMID: 31058117 PMCID: PMC6478887 DOI: 10.3389/fped.2019.00135] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Accepted: 03/22/2019] [Indexed: 01/10/2023] Open
Abstract
Fibroblast growth factor 23 (FGF 23), an endocrine hormone regulating the homeostasis of phosphate and vitamin D, has been shown to play a role in cardiovascular disease. Increased blood FGF 23 is found to be associated with elevated blood pressure in adults. However, measurement of FGF 23 in hypertensive children has not been documented. In this study, a total of 98 children with primary hypertension and 37 controls were recruited, and blood FGF 23 was comparatively investigated. Additionally, FGF 23 levels were compared between the subgroups of patients after hypertensive children were sub-grouped according to their cardiac geometry, hypertension stages, insulin levels, and weight. The case group had a FGF 23 level of 48.99 (16.42), expressed as the median (the interquartile range), significantly higher than the 41.72 (7.05) from the control group (p = 0.0002). While no remarkable differences were observed in FGF 23 levels between non-obese and obese hypertensive children, between patients with stage 1 and stage 2 hypertension, or between patients with normal and high insulin levels; hypertensive children with abnormal cardiac geometry had significantly higher levels of FGF 23 than patients with normal cardiac geometry (p = 0.0085). Our data revealed for the first time that hypertensive children have higher levels of FGF 23. Further studies are needed to examine if lowering FGF 23 improves the cardiac geometry in hypertensive children with higher FGF 23.
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Affiliation(s)
- Yao Lin
- Department of Pediatric Cardiology, Children's Hospital, Capital Institute of Pediatrics, Beijing, China
| | - Lin Shi
- Department of Pediatric Cardiology, Children's Hospital, Capital Institute of Pediatrics, Beijing, China
| | - Yanyan Liu
- Department of Pediatric Cardiology, Children's Hospital, Capital Institute of Pediatrics, Beijing, China
| | - Hongwei Zhang
- Department of Pediatric Cardiology, Children's Hospital, Capital Institute of Pediatrics, Beijing, China
| | - Yang Liu
- Department of Pediatric Cardiology, Children's Hospital, Capital Institute of Pediatrics, Beijing, China
| | - Xiaolan Huang
- Central Diagnostic Laboratory, Children's Hospital, Capital Institute of Pediatrics, Beijing, China
| | - Dongqing Hou
- Department of Epidemiology, Children's Hospital, Capital Institute of Pediatrics, Beijing, China
| | - Mingming Zhang
- Department of Pediatric Cardiology, Children's Hospital, Capital Institute of Pediatrics, Beijing, China
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27
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Uremic Toxins and Clinical Outcomes: The Impact of Kidney Transplantation. Toxins (Basel) 2018; 10:toxins10060229. [PMID: 29874852 PMCID: PMC6024850 DOI: 10.3390/toxins10060229] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Revised: 05/31/2018] [Accepted: 06/01/2018] [Indexed: 12/13/2022] Open
Abstract
Non-transplanted and transplanted patients with chronic kidney disease (CKD) differ in terms of mortality and the risk of clinical events. This difference is probably due to the difference of both traditional and non-traditional risk factors. Uremic retention solutes may constitute important non-traditional risk factors in this population. In the present review, we selected a set of uremic toxins that have been associated with harmful effects, and are an appealing target for adjuvant therapy in CKD. For each toxin reviewed here, relevant studies were selected and the relationship with hard clinical outcomes of uremic toxins were compared between non-transplanted CKD patients and transplanted patients taking into account the level of glomerular filtration rate in these two situations.
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Tranæus Lindblad Y, Olauson H, Vavilis G, Hammar U, Herthelius M, Axelsson J, Bárány P. The FGF23-Klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease-a prospective cohort study. Pediatr Nephrol 2018; 33:147-157. [PMID: 28795324 PMCID: PMC5700222 DOI: 10.1007/s00467-017-3766-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 07/13/2017] [Accepted: 07/14/2017] [Indexed: 01/09/2023]
Abstract
BACKGROUND Chronic kidney disease-associated mineral bone disorder (CKD-MBD) is common in pediatric kidney disease patients and a risk factor for future cardiovascular disease (CVD). Fibroblast growth factor-23 (FGF23) and Klotho are novel key players in CKD-MBD, and has been suggested to be involved in the development of CVD. METHODS This prospective cohort study included 74 pediatric patients; 31 with CKD (age range 0.8-18.8 years, glomerular filtration rate (GFR) range 9-68 mL/min/1.73 m2) and 43 transplanted patients (CKD-T; age range 3.3-17.7 years, GFR range 10-99 mL/min/1.73 m2) examined annually for 3 years. We assessed longitudinal patterns and predictors of FGF23 and soluble Klotho, as well as associations to cardiac remodeling and function using echocardiographic pulse wave Doppler (PWD) and color-coded tissue Doppler imaging (cc-TDI). RESULTS The prevalence of high FGF23 levels (≥95th percentile) was 60% in CKD and 42% in CKD-T patients, despite a low prevalence of hyperphosphatemia and normal Klotho levels. Low GFR at baseline was a predictor for high mean log FGF23 during follow-up in CKD and CKD-T patients (β = -0.2, p < 0.001). A high log FGF23 z-score longitudinally was borderline significantly associated with elevated left ventricular mass index (LVMI) in CKD patients (β = 1.8, p = 0.06). In addition, high log FGF23 (β = -0.43, p = 0.01) and low log Klotho (β = 0.44, p = 0.006) over time were associated with a worse left ventricular diastolic function (cc-TDI e'/a') in CKD-T patients. CONCLUSIONS In pediatric CKD and CKD-T patients, the FGF23 level increase and Klotho level decrease with progressing renal failure, despite well-controlled phosphate levels. Following adjustments, both high FGF23 and low Klotho levels were strongly associated with a worse left ventricular diastolic function longitudinally. The potential role of FGF23 and Klotho in cardiac morbidity in pediatric CKD requires further investigation.
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Affiliation(s)
- Ylva Tranæus Lindblad
- Division of Pediatrics, Department of Clinical Sciences, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden. .,Astrid Lindgren Children's Hospital, Huddinge BUMM, Paradistorget 4, 5tr, S-141 47, Huddinge, Sweden. .,Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden.
| | - Hannes Olauson
- 0000 0004 1937 0626grid.4714.6Division of Renal Medicine, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Georgios Vavilis
- 0000 0000 9241 5705grid.24381.3cDivision of Emergency Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Ulf Hammar
- 0000 0004 1937 0626grid.4714.6Institute of Environmental Medicine and Unit of Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Maria Herthelius
- 0000 0004 1937 0626grid.4714.6Division of Pediatrics, Department of Clinical Sciences, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden ,0000 0000 9241 5705grid.24381.3cDepartment of Pediatrics, Karolinska University Hospital, Stockholm, Sweden
| | - Jonas Axelsson
- 0000 0000 9241 5705grid.24381.3cDepartment of Immunology, Karolinska University Hospital, Stockholm, Sweden ,0000 0004 1937 0626grid.4714.6Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Peter Bárány
- 0000 0004 1937 0626grid.4714.6Division of Renal Medicine, CLINTEC, Karolinska Institutet, Stockholm, Sweden ,0000 0000 9241 5705grid.24381.3cDepartment of Renal Medicine, Karolinska University Hospital, Stockholm, Sweden
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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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30
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Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney Int 2016; 90:985-996. [PMID: 27457912 DOI: 10.1016/j.kint.2016.05.019] [Citation(s) in RCA: 275] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 04/26/2016] [Accepted: 05/19/2016] [Indexed: 12/14/2022]
Abstract
Patients with chronic kidney disease (CKD) develop increased levels of the phosphate-regulating hormone, fibroblast growth factor (FGF) 23, that are associated with a higher risk of mortality. Increases in inflammatory markers are another common feature that predicts poor clinical outcomes. Elevated FGF23 is associated with higher circulating levels of inflammatory cytokines in CKD, which can stimulate osteocyte production of FGF23. Here, we studied whether FGF23 can directly stimulate hepatic production of inflammatory cytokines in the absence of α-klotho, an FGF23 coreceptor in the kidney that is not expressed by hepatocytes. By activating FGF receptor isoform 4 (FGFR4), FGF23 stimulated calcineurin signaling in cultured hepatocytes, which increased the expression and secretion of inflammatory cytokines, including C-reactive protein. Elevating serum FGF23 levels increased hepatic and circulating levels of C-reactive protein in wild-type mice, but not in FGFR4 knockout mice. Administration of an isoform-specific FGFR4 blocking antibody reduced hepatic and circulating levels of C-reactive protein in the 5/6 nephrectomy rat model of CKD. Thus, FGF23 can directly stimulate hepatic secretion of inflammatory cytokines. Our findings indicate a novel mechanism of chronic inflammation in patients with CKD and suggest that FGFR4 blockade might have therapeutic anti-inflammatory effects in CKD.
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Abstract
The last 25 years have been characterized by dramatic improvements in short-term patient and allograft survival after kidney transplantation. Long-term patient and allograft survival remains limited by cardiovascular disease and chronic allograft injury, among other factors. Cardiovascular disease remains a significant contributor to mortality in native chronic kidney disease as well as cardiovascular mortality in chronic kidney disease more than doubles that of the general population. The chronic kidney disease (CKD)-mineral bone disorder (MBD) is a syndrome recently coined to embody the biochemical, skeletal, and cardiovascular pathophysiology that results from disrupting the complex systems biology between the kidney, skeleton, and cardiovascular system in native and transplant kidney disease. The CKD-MBD is a unique kidney disease-specific syndrome containing novel cardiovascular risk factors, with an impact reaching far beyond traditional notions of renal osteodystrophy and hyperparathyroidism. This overview reviews current knowledge of the pathophysiology of the CKD-MBD, including emerging concepts surrounding the importance of circulating pathogenic factors released from the injured kidney that directly cause cardiovascular disease in native and transplant chronic kidney disease, with potential application to mechanisms of chronic allograft injury and vasculopathy.
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Malyszko J, Koc-Zorawska E, Matuszkiewicz-Rowinska J, Malyszko J. FGF23 and Klotho in relation to markers of endothelial dysfunction in kidney transplant recipients. Transplant Proc 2015; 46:2647-50. [PMID: 25380886 DOI: 10.1016/j.transproceed.2014.09.015] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Fibroblast growth factor (FGF) 23 is a newly discovered member of the FGF family. Klotho is a cofactor of FGF23. Activation of the FGF23-Klotho system is responsible for negative phosphate balance. In addition, FGF23 appears to be a risk factor for cardiovascular complications. The aim of this study was to assess levels of FGF23 and Klotho in stable kidney transplant recipients on triple immunosuppressive therapy in relation to comorbidities and markers endothelial dysfunction. Healthy volunteers served as a control group. METHODS Hemoglobin, urea, and creatinine were studied with the use of standard laboratory methods in the hospital central laboratory. We assessed FGF23 and Klotho, markers of endothelial function/injury von Willebrand factor (vWF), intercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), and interleukin (IL) 6, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and copeptin with the use of commercially available assays. RESULTS FGF23 was significantly higher and Klotho significantly lower in kidney transplant recipients compared with healthy volunteers. FGF23 correlated with copeptin (r = 0.28; P < .05), IL-6 (r = 0.39; P < .01), VCAM (r = 0.36; P < .01), time after transplantation (r = 0.31; P < .05), platelet count (r = 0.31; P < .05), mean corpuscular volume (r = -0.40; P < .01), and phosphate (r = 0.31; P < .05). Klotho correlated with NT-proBNP (r = 0.38; P < .01), vWF (r = -0.26; P < .05), calcium (r = -0.39; P < .01), and age (r = 0.45; P < .001). FGF23 was significantly higher and Klotho significantly lower in patients with estimated glomerular filtration rate (eGFR) >60 mL/min compared with patients with eGFR <60 mL/min. CONCLUSIONS Disturbances in the FGF23-Klotho system appeared to be related to the endothelial cell injury. Thus they are involved not only in pathogenesis of the metabolic bone disease but also in cardiovascular complications, particularly in kidney disease.
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Affiliation(s)
- Jolanta Malyszko
- 2nd Department of Nephrology, Medical University, Bialystok, Poland.
| | - E Koc-Zorawska
- 2nd Department of Nephrology, Medical University, Bialystok, Poland
| | - J Matuszkiewicz-Rowinska
- Department of Nephrology, Internal Medicine and Dialysis Therapy, Medical University, Warsaw, Poland
| | - Jacek Malyszko
- 2nd Department of Nephrology, Medical University, Bialystok, Poland
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Hu P, Huang BY, Xia X, Xuan Q, Hu B, Qin YH. Therapeutic effect of CNP on renal osteodystrophy by antagonizing the FGF-23/MAPK pathway. J Recept Signal Transduct Res 2015; 36:213-9. [DOI: 10.3109/10799893.2015.1075041] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Sinha MD, Turner C, Booth CJ, Waller S, Rasmussen P, Goldsmith DJA, Simpson JM. Relationship of FGF23 to indexed left ventricular mass in children with non-dialysis stages of chronic kidney disease. Pediatr Nephrol 2015; 30:1843-52. [PMID: 25975437 DOI: 10.1007/s00467-015-3125-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2014] [Revised: 04/13/2015] [Accepted: 04/28/2015] [Indexed: 01/05/2023]
Abstract
BACKGROUND The aim of this study was to evaluate the association of serum intact fibroblast growth factor 23 (FGF23) concentrations with indexed left ventricular mass in children with non-dialysis stages 3-5 of chronic kidney disease (CKD). METHODS The study cohort comprised 83 children (51 boys; mean age 12.1 ± 3.2 years) with a mean estimated glomerular filtration rate (eGFR) of 32.3 ± 14.6 ml/min/1.73 m(2) who underwent clinic and ambulatory blood pressure measurement (ABPM), echocardiography and evaluation of biochemical markers of CKD-associated mineral bone disease. RESULTS The mean left ventricular mass index (LVMI) was 35.9 ± 8.5 g/m(2.7) (± standard deviation), with 30 (36.1 %) children showing left ventricular hypertrophy (LVH), all eccentric, as defined using age-specific criteria. For all subjects, the mean FGF23 concentration was 142.2 ± 204.4 ng/l and the normalised distribution following log transformation was 1.94 ± 0.39. There was significant univariate correlation of LVMI with GFR, body mass index (BMI) z-score and calcium intake, but not with 24-h systolic ABPM z-score, log intact parathyroid hormone or log FGF23. On multivariate analysis following adjustment for confounders, only elemental calcium content (g/kg/day) estimated from prescribed calcium-based phosphate binder dose (β = 154.9, p < 0.001) and BMI z-score (β = 2.397, p = 0.003) maintained a significant positive relationship with LVMI (model r (2) = 0.225). CONCLUSIONS We observed no significant relationship of FGF23 with LVMI. Larger studies in children are needed to clarify the roles of calcium-containing phosphate binders and FGF23 with LV mass and their roles in the evolution of the development of adverse cardiovascular outcomes.
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Affiliation(s)
- Manish D Sinha
- Department of Paediatric Nephrology, Evelina London Children's Hospital, Guys & St Thomas' NHS Foundation Trust, Room 64, Sky Level, Westminster Bridge Road, London, SE1 7EH, UK,
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Abstract
Dysregulated phosphate metabolism is a common consequence of chronic kidney disease, and is characterized by a high circulating level of fibroblast growth factor (FGF)-23, hyperparathyroidism, and hyperphosphataemia. Kidney transplantation can elicit specific alterations to phosphate metabolism that evolve over time, ranging from severe hypophosphataemia (<0.5 mmol/l) to hyperphosphataemia (>1.50 mmol/l) and high FGF-23 levels. The majority of renal transplant recipients develop hypophosphataemia during the first 3 months after transplantation as a consequence of relatively slow adaptation of FGF-23 and parathyroid hormone levels to restored renal function, and the influence of immunosuppressive drugs. By 3-12 months after transplantation, phosphate homeostasis is at least partially restored in the majority of recipients, which is paralleled by a substantially reduced risk of cardiovascular-associated morbidity and mortality compared with the pre-transplantation setting. Many renal transplant recipients, however, exhibit persistent abnormalities in phosphate homeostasis, which is often due to multifactorial causes, and may contribute to adverse outcomes on the cardiovascular system, kidney, and bone. Dietary and pharmacologic interventions might improve phosphate homeostasis in renal transplant recipients, but additional insight into the pathophysiology of transplantation-associated abnormalities in phosphate homeostasis is needed to further optimize disease management and improve prognosis for renal transplant recipients.
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Pereira RC, Valta H, Tumber N, Salusky IB, Jalanko H, Mäkitie O, Wesseling Perry K. Altered Osteocyte-Specific Protein Expression in Bone after Childhood Solid Organ Transplantation. PLoS One 2015; 10:e0138156. [PMID: 26390291 PMCID: PMC4577074 DOI: 10.1371/journal.pone.0138156] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Accepted: 08/25/2015] [Indexed: 01/30/2023] Open
Abstract
Background Bone fragility is common post solid organ transplantation but little is known about bone pathology on a tissue level. Abnormal osteocytic protein expression has been linked to compromised bone health in chronic kidney disease (CKD) and immunosuppressant medications may impact osteocyte function. Methods Transiliac bone biopsies were obtained from 22 pediatric solid organ allograft recipients (average age 15.6 years) an average of 6.3 ± 1.2 years after transplantation and from 12 pediatric pre-dialysis CKD patients (average age 13.2 years). Histomorphometry and immunohistochemistry for FGF23, DMP1, sclerostin, and osteopontin were performed on all biopsies. Results FGF23 and sclerostin were increased in transplant recipients relative to non-transplant CKD, regardless of the type of allograft received and despite, in the case of liver and heart recipients, a higher GFR. Bone DMP1 expression was higher in liver or heart than in kidney recipients, concomitant with higher serum phosphate values. Osteopontin expression was higher in CKD than in transplant recipients (p<0.01). Bone FGF23 and sclerostin correlated directly (r = 0.38, p<0.05); bone FGF23 expression and osteoid thickness correlated inversely (r = - 0.46, p<0.01). Conclusions Solid-organ transplantation is associated with increased FGF23 and sclerostin expression. The contribution of these findings to compromised bone health post transplantation warrants further evaluation.
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Affiliation(s)
- Renata C. Pereira
- Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, United States of America
| | - Helena Valta
- Children's Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
| | - Navdeep Tumber
- Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, United States of America
| | - Isidro B. Salusky
- Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, United States of America
| | - Hannu Jalanko
- Children's Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
| | - Outi Mäkitie
- Children's Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
- Folkhälsan Research Center, Helsinki, Finland
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Katherine Wesseling Perry
- Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, United States of America
- * E-mail:
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The consequences of pediatric renal transplantation on bone metabolism and growth. Curr Opin Organ Transplant 2015; 18:555-62. [PMID: 23995376 DOI: 10.1097/mot.0b013e3283651b21] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW During childhood, growth retardation, decreased final height and renal osteodystrophy are common complications of chronic kidney disease (CKD). These problems remain present in patients undergoing renal transplantation, even though steroid-sparing strategies are more widely used. In this context, achieving normal height and growth in children after transplantation is a crucial issue for both quality of life and self-esteem. The aim of this review is to provide an overview of pathophysiology of CKD-mineral bone disorder (MBD) in children undergoing renal transplantation and to propose keypoints for its daily management. RECENT FINDINGS In adults, calcimimetics are effective for posttransplant hyperparathyroidism, but data are missing in the pediatric population. Fibroblast growth factor 23 levels are associated with increased risk of rejection, but the underlying mechanisms remain unclear. A recent meta-analysis also demonstrated the effectiveness of rhGH therapy in short transplanted children. SUMMARY In 2013, the daily clinical management of CKD-MBD in transplanted children should still focus on simple objectives: to optimize renal function, to develop and promote steroid-sparing strategies, to provide optimal nutritional support to maximize final height and avoid bone deformations, to equilibrate calcium/phosphate metabolism so as to provide acceptable bone quality and cardiovascular status, to correct all metabolic and clinical abnormalities that can worsen both bone and growth (mainly metabolic acidosis, anemia and malnutrition), promote good lifestyle habits (adequate calcium intake, regular physical activity, no sodas consumption, no tobacco exposure) and eventually to correct native vitamin D deficiency (target of 25-vitamin D >75 nmol/l).
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Wesseling-Perry K. The Authors Reply. Kidney Int 2015; 88:640-1. [PMID: 26323080 DOI: 10.1038/ki.2015.219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Hamo S, Freychet C, Bertholet-Thomas A, Poulat AL, Cochat P, Vuillerot C, Bacchetta J. [Vitamin D supplementation: not too much, not too little!]. Arch Pediatr 2015; 22:868-71. [PMID: 26141804 DOI: 10.1016/j.arcped.2015.04.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 02/23/2015] [Accepted: 04/28/2015] [Indexed: 10/23/2022]
Abstract
Vitamin D deficiency is common in the general population and even more frequent in patients with chronic diseases. The prevention of rickets with native vitamin D supplementation is one of the oldest and most effective prophylactic measures ever reported in medicine, leading to an almost complete eradication of vitamin D-deficient rickets in developed countries. We report on two children with vitamin D abnormalities: the first, 10-year-old child developed rickets without any vitamin D supplementation despite different risk factors (autism, ethnicity, nutritional problems, chronic antiepileptic therapies). In contrast, the second, 8-month-old child received double doses of native vitamin D from birth for several months and was referred for acute and symptomatic hypercalcemia. As such, vitamin D supplementation must follow specific rules: neither too much nor too little! We also discuss the emergence of "new" genetic diseases such as mutations in the 24-hydroxylase (CYP24A1) gene inducing neonatal hypercalcemia and nephrocalcinosis: we believe that before prescribing conventional vitamin D supplementation as recommended by the national guidelines, pediatricians should quickly rule out a potential genetic abnormality in phosphate/calcium metabolism (namely a history of lithiasis or hypercalcemia) that would lead to further biological investigations.
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Affiliation(s)
- S Hamo
- Service de néphrologie rhumatologie dermatologie pédiatriques, centre de référence des maladies rénales rares, hôpital Femme-Mère-Enfant, 59, boulevard Pinel, 69677 Bron cedex, France
| | - C Freychet
- Service de néphrologie rhumatologie dermatologie pédiatriques, centre de référence des maladies rénales rares, hôpital Femme-Mère-Enfant, 59, boulevard Pinel, 69677 Bron cedex, France; Faculté de médecine Lyon-Est, université de Lyon, 69008 Lyon, France
| | - A Bertholet-Thomas
- Service de néphrologie rhumatologie dermatologie pédiatriques, centre de référence des maladies rénales rares, hôpital Femme-Mère-Enfant, 59, boulevard Pinel, 69677 Bron cedex, France
| | - A-L Poulat
- Service de neurologie pédiatrique, hôpital Femme-Mère-Enfant, 69677 Bron cedex, France
| | - P Cochat
- Service de néphrologie rhumatologie dermatologie pédiatriques, centre de référence des maladies rénales rares, hôpital Femme-Mère-Enfant, 59, boulevard Pinel, 69677 Bron cedex, France; Faculté de médecine Lyon-Est, université de Lyon, 69008 Lyon, France
| | - C Vuillerot
- Faculté de médecine Lyon-Est, université de Lyon, 69008 Lyon, France; Service de neurologie pédiatrique, hôpital Femme-Mère-Enfant, 69677 Bron cedex, France; Service de rééducation fonctionnelle pédiatrique, hôpital Femme-Mère-Enfant, 69677 Bron cedex, France
| | - J Bacchetta
- Service de néphrologie rhumatologie dermatologie pédiatriques, centre de référence des maladies rénales rares, hôpital Femme-Mère-Enfant, 59, boulevard Pinel, 69677 Bron cedex, France; Faculté de médecine Lyon-Est, université de Lyon, 69008 Lyon, France.
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Abstract
Traditionally, control of phosphorus in the body has been considered secondary to the tighter control of calcium by parathyroid hormone and vitamin D. However, over the past decade, substantial advances have been made in understanding the control of phosphorus by the so-called phosphatonin system, the lynchpin of which is fibroblast growth factor 23 (FGF23). FGF23 binds to the klotho/FGFR1c receptor complex in renal tubular epithelial cells, leading to upregulation of Na/Pi cotransporters and subsequent excretion of phosphorus from the body. In addition, FGF23 inhibits parathyroid hormone and the renal 1α-hydroxylase enzyme, while it stimulates 24-hydroxylase, leading to decreased 1,25-dihydroxyvitamin D3. FGF23 is intimately involved in the pathogenesis of a number of diseases, particularly the hereditary hypophosphatemic rickets group and chronic kidney disease, and is a target for the development of new treatments in human medicine. Little work has been done on FGF23 or the other phosphatonins in veterinary medicine, but increases in FGF23 are seen with chronic kidney disease in cats, and increased FGF23 expression has been found in soft tissue sarcomas in dogs.
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Affiliation(s)
- M. R. Hardcastle
- Gribbles Veterinary Pathology Ltd, Mt Wellington, Auckland, New Zealand
| | - K. E. Dittmer
- Animal and Biomedical Sciences, Institute of Veterinary, Massey University, Palmerston North, New Zealand
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Intestinal phosphate transport: a therapeutic target in chronic kidney disease and beyond? Pediatr Nephrol 2015; 30:363-71. [PMID: 24496589 DOI: 10.1007/s00467-014-2759-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Revised: 12/11/2013] [Accepted: 01/08/2014] [Indexed: 12/22/2022]
Abstract
Hyperphosphatemia is a serious complication of late-stage chronic kidney disease (CKD), contributing to the increased cardiovascular morbidity and mortality seen in this patient group. Results from retrospective studies suggest that small increases in serum phosphate concentration, within the normal or near-normal range, also correlate with increased cardiovascular morbidity and mortality and have led to the suggestion that detection and preventative treatment of positive phosphate balance is important in healthy individuals as well as in those with CKD. Phosphate homeostasis is maintained by the crosstalk between intestinal phosphate absorption and renal phosphate excretion; however, relatively little is known about the mechanisms of intestinal phosphate transport. Our current understanding is that the intestinal type II sodium phosphate cotransporter, NaPi-IIb, plays a significant role in absorption. It may also be involved in the sensing of dietary phosphate composition and the release of hormonal factors that modulate renal phosphate reabsorption to achieve phosphate balance. Interestingly, studies using NaPi-IIb knockout mice with adenine-induced CKD show only partial attenuation of hyperphosphatemia, suggesting that an additional sodium-independent pathway is involved in phosphate absorption. The aim of this review is to discuss our current knowledge of the processes and role of the intestine in phosphate homeostasis and to provide evidence that this organ could be targeted for the treatment of hypophosphatemia and hyperphosphatemia.
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Bonthuis M, Busutti M, van Stralen KJ, Jager KJ, Baiko S, Bakkaloğlu S, Battelino N, Gaydarova M, Gianoglio B, Parvex P, Gomes C, Heaf JG, Podracka L, Kuzmanovska D, Molchanova MS, Pankratenko TE, Papachristou F, Reusz G, Sanahuja MJ, Shroff R, Groothoff JW, Schaefer F, Verrina E. Mineral metabolism in European children living with a renal transplant: a European society for paediatric nephrology/european renal association-European dialysis and transplant association registry study. Clin J Am Soc Nephrol 2015; 10:767-75. [PMID: 25710805 DOI: 10.2215/cjn.06200614] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Accepted: 01/13/2015] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND OBJECTIVES Data on mineral metabolism in pediatric renal transplant recipients largely arise from small single-center studies. In adult patients, abnormal mineral levels are related to a higher risk of graft failure. This study used data from the European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association Registry to study the prevalence and potential determinants of mineral abnormalities, as well as the predictive value of a disturbed mineral level on graft survival in a large cohort of European pediatric renal transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study included 1237 children (0-17 years) from 10 European countries, who had serum calcium, phosphorus, and parathyroid hormone measurements from 2000 onward. Abnormalities of mineral metabolism were defined according to European guidelines on prevention and treatment of renal osteodystrophy in children on chronic renal failure. RESULTS Abnormal serum phosphorus levels were observed in 25% (14% hypophosphatemia and 11% hyperphosphatemia), altered serum calcium in 30% (19% hypocalcemia, 11% hypercalcemia), and hyperparathyroidism in 41% of the patients. A longer time since transplantation was associated with a lower risk of having mineral levels above target range. Serum phosphorus levels were inversely associated with eGFR, and levels above the recommended targets were associated with a higher risk of graft failure independently of eGFR. CONCLUSIONS Abnormalities in mineral metabolism are common after pediatric renal transplantation in Europe and are associated with graft dysfunction.
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Affiliation(s)
- Marjolein Bonthuis
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - Marco Busutti
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - Karlijn J van Stralen
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material.
| | - Kitty J Jager
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - Sergey Baiko
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - Sevcan Bakkaloğlu
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - Nina Battelino
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - Maria Gaydarova
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - Bruno Gianoglio
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - Paloma Parvex
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - Clara Gomes
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - James G Heaf
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - Ludmila Podracka
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - Dafina Kuzmanovska
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - Maria S Molchanova
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - Tatiana E Pankratenko
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - Fotios Papachristou
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - György Reusz
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - Maria José Sanahuja
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - Rukshana Shroff
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - Jaap W Groothoff
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - Franz Schaefer
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
| | - Enrico Verrina
- Due to the number of contributing authors,the affiliations are provided in the Supplemental Material
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Markers of bone metabolism are affected by renal function and growth hormone therapy in children with chronic kidney disease. PLoS One 2015; 10:e0113482. [PMID: 25659076 PMCID: PMC4319910 DOI: 10.1371/journal.pone.0113482] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Accepted: 10/28/2014] [Indexed: 12/14/2022] Open
Abstract
Objectives The extent and relevance of altered bone metabolism for statural growth in children with chronic kidney disease is controversial. We analyzed the impact of renal dysfunction and recombinant growth hormone therapy on a panel of serum markers of bone metabolism in a large pediatric chronic kidney disease cohort. Methods Bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase 5b (TRAP5b), sclerostin and C-terminal FGF-23 (cFGF23) normalized for age and sex were analyzed in 556 children aged 6–18 years with an estimated glomerular filtration rate (eGFR) of 10–60 ml/min/1.73m2. 41 children receiving recombinant growth hormone therapy were compared to an untreated matched control group. Results Standardized levels of BAP, TRAP5b and cFGF-23 were increased whereas sclerostin was reduced. BAP was correlated positively and cFGF-23 inversely with eGFR. Intact serum parathormone was an independent positive predictor of BAP and TRAP5b and negatively associated with sclerostin. BAP and TRAP5B were negatively affected by increased C-reactive protein levels. In children receiving recombinant growth hormone, BAP was higher and TRAP5b lower than in untreated controls. Sclerostin levels were in the normal range and higher than in untreated controls. Serum sclerostin and cFGF-23 independently predicted height standard deviation score, and BAP and TRAP5b the prospective change in height standard deviation score. Conclusion Markers of bone metabolism indicate a high-bone turnover state in children with chronic kidney disease. Growth hormone induces an osteoanabolic pattern and normalizes osteocyte activity. The osteocyte markers cFGF23 and sclerostin are associated with standardized height, and the markers of bone turnover predict height velocity.
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Bacchetta J, Chun RF, Gales B, Zaritsky JJ, Leroy S, Wesseling-Perry K, Boregaard N, Rastogi A, Salusky IB, Hewison M. Antibacterial responses by peritoneal macrophages are enhanced following vitamin D supplementation. PLoS One 2014; 9:e116530. [PMID: 25549329 PMCID: PMC4280222 DOI: 10.1371/journal.pone.0116530] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 12/08/2014] [Indexed: 12/30/2022] Open
Abstract
Patients with chronic kidney disease (CKD), who usually display low serum 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D), are at high risk of infection, notably those undergoing peritoneal dialysis (PD). We hypothesized that peritoneal macrophages from PD patients are an important target for vitamin D-induced antibacterial activity. Dialysate effluent fluid was obtained from 27 non-infected PD patients. Flow cytometry indicated that PD cells were mainly monocytic (37.9±17.7% cells CD14+/CD45+). Ex vivo analyses showed that PD cells treated with 25D (100 nM, 6 hrs) or 1,25D (5 nM, 6 hrs) induced mRNA for antibacterial cathelicidin (CAMP) but conversely suppressed mRNA for hepcidin (HAMP). PD cells from patients with peritonitis (n = 3) showed higher baseline expression of CAMP (18-fold±9, p<0.05) and HAMP (64-fold±7) relative to cells from non-infected patients. In 12 non-infected PD patients, oral supplementation with a single dose of vitamin D2 (100,000 IU) increased serum levels of 25D from 18±8 to 41±15 ng/ml (p = 0.002). This had no significant effect on PD cell CD14/CD45 expression, but mRNA for HAMP was suppressed significantly (0.5-fold, p = 0.04). Adjustment for PD cell CD14/CD45 expression using a mixed linear statistical model also revealed increased expression of CAMP (mRNA in PD cells and protein in effluent) in vitamin D-supplemented patients. These data show for the first time that vitamin D supplementation in vitro and in vivo promotes innate immune responses that may enhance macrophage antibacterial responses in patients undergoing PD. This highlights a potentially important function for vitamin D in preventing infection-related complications in CKD.
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Affiliation(s)
- Justine Bacchetta
- Orthopedic Hospital Research Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America
- Department of Pediatrics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
- Centre de Référence des Maladies Rénales Rares, Institut de Génomique Fonctionnelle à l’Ecole Normale Supérieure de Lyon et Université de Lyon, Lyon, France
| | - Rene F. Chun
- Orthopedic Hospital Research Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America
| | - Barbara Gales
- Department of Pediatrics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
| | - Joshua J. Zaritsky
- Department of Pediatrics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
| | - Sandrine Leroy
- Unité d’épidémiologie des maladies émergentes, Institut Pasteur, Paris, France
| | - Katherine Wesseling-Perry
- Department of Pediatrics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
| | - Niels Boregaard
- Department of Hematology, University of Copenhagen, Copenhagen, Denmark
| | - Anjay Rastogi
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
| | - Isidro B. Salusky
- Department of Pediatrics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
| | - Martin Hewison
- Orthopedic Hospital Research Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America
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Wolf I, Shahmoon S, Ben Ami M, Levy-Shraga Y, Mazor-Aronovitch K, Pinhas-Hamiel O, Yeshayahu Y, Hemi R, Kanety H, Rubinek T, Modan-Moses D. Association between decreased klotho blood levels and organic growth hormone deficiency in children with growth impairment. PLoS One 2014; 9:e107174. [PMID: 25198618 PMCID: PMC4157849 DOI: 10.1371/journal.pone.0107174] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Accepted: 08/07/2014] [Indexed: 02/05/2023] Open
Abstract
Objective Klotho is an aging-modulating protein expressed mainly in the kidneys and choroid plexus, which can also be shed, released into the circulation and act as a hormone. Klotho deficient mice are smaller compared to their wild-type counterparts and their somatotropes show marked atrophy and reduced number of secretory granules. Recent data also indicated an association between klotho levels and growth hormone (GH) levels in acromegaly. We aimed to study the association between klotho levels and GH deficiency (GHD) in children with growth impairment. Design Prospective study comprising 99 children and adolescents (aged 9.0±3.7 years, 49 male) undergoing GH stimulation tests for short stature (height-SDS = −2.1±0.6). Klotho serum levels were measured using an α-klotho ELISA kit. Results Klotho levels were significantly lower (p<0.001) among children with organic GHD (n = 11, 727±273 pg/ml) compared to both GH sufficient participants (n = 59, 1497±754 pg/ml) and those with idiopathic GHD (n = 29, 1645±778 pg/ml). The difference between GHS children and children with idiopathic GHD was not significant. Klotho levels positively correlated with IGF-1- standard deviation scores (SDS) (R = 0.45, p<0.001), but were not associated with gender, pubertal status, age or anthropometric measurements. Conclusions We have shown, for the first time, an association between low serum klotho levels and organic GHD. If validated by additional studies, serum klotho may serve as novel biomarker of organic GHD.
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Affiliation(s)
- Ido Wolf
- Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shiri Shahmoon
- Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Michal Ben Ami
- Pediatric Endocrinology and Diabetes Unit, The Edmond and Lily Safra Children’s Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel
| | - Yael Levy-Shraga
- Pediatric Endocrinology and Diabetes Unit, The Edmond and Lily Safra Children’s Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel
| | - Kineret Mazor-Aronovitch
- Pediatric Endocrinology and Diabetes Unit, The Edmond and Lily Safra Children’s Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel
| | - Orit Pinhas-Hamiel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Pediatric Endocrinology and Diabetes Unit, The Edmond and Lily Safra Children’s Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel
| | - Yonatan Yeshayahu
- Pediatric Endocrinology and Diabetes Unit, The Edmond and Lily Safra Children’s Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel
| | - Rina Hemi
- Institute of Endocrinology, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel
| | - Hannah Kanety
- Institute of Endocrinology, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel
| | - Tami Rubinek
- Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Dalit Modan-Moses
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Pediatric Endocrinology and Diabetes Unit, The Edmond and Lily Safra Children’s Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel
- * E-mail:
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Gkentzi D, Efthymiadou A, Kritikou D, Chrysis D. Fibroblast growth factor 23 and Klotho serum levels in healthy children. Bone 2014; 66:8-14. [PMID: 24880094 DOI: 10.1016/j.bone.2014.05.012] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Revised: 05/13/2014] [Accepted: 05/22/2014] [Indexed: 12/18/2022]
Abstract
Data for fibroblast growth factor 23 (FGF23) and particularly for Klotho in healthy children are limited. We aimed to investigate the relationship between FGF23 and Klotho with age and TmP/GFR and to evaluate parameters that might affect FGF23 and Klotho. In 159 healthy children (82 boys) with a mean±SD age of 8.78±3.47years we measured FGF23 (intact FGF23/iFGF23 and C-terminal FGF23/cFGF23) and soluble aKlotho serum levels by ELISA. Mean±SD value for cFGF23, was 51.14±12.79 RU/ml whereas median (range) values for iFGF23 and Klotho were 35 (8.8, 120) pg/ml and 1945 (372, 5866) pg/ml respectively. Neither FGF23 nor Klotho were significantly associated with age. Pubertal children had higher Klotho than prepubertal (p<0.05), and girls had higher levels of cFGF23 (p<0.05) and Klotho (p<0.001) than boys. Serum phosphate and TmP/GFR were positively associated with cFGF23 (p<0.01 and p<0.001), iFGF23 (p<0.05 and p<0.001) and Klotho (p<0.05 and p<0.01). Klotho was positively correlated with IGF-I (p<0.0001) and 1,25 (OH)2 vitamin D (p<0.05). In this study we provide data on cFGF23, iFGF23, and Klotho measured simultaneously in healthy children. The positive association of serum phosphate and TmP/GFR with FGF23 and Klotho suggests that they have a counterregulatory effect on phosphate homeostasis. The strong association of Klotho with IGF-I could indicate a role of Klotho in linear growth through phosphate regulation, but further studies are required.
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Affiliation(s)
- Despoina Gkentzi
- Department of Pediatrics, Medical School, University of Patras, Rio, Greece.
| | - Alexandra Efthymiadou
- Pediatric Endocrine Unit, Department of Pediatrics, Medical School, University of Patras, Rio, Greece
| | - Dimitra Kritikou
- Pediatric Endocrine Unit, Department of Pediatrics, Medical School, University of Patras, Rio, Greece
| | - Dionisios Chrysis
- Pediatric Endocrine Unit, Department of Pediatrics, Medical School, University of Patras, Rio, Greece
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Cano FJ, Freundlich M, Ceballos ML, Rojo AP, Azocar MA, Delgado IO, Ibacache MJ, Delucchi MA, Lillo AM, Irarrázabal CE, Ugarte MF. Longitudinal FGF23 and Klotho axis characterization in children treated with chronic peritoneal dialysis. Clin Kidney J 2014; 7:457-63. [PMID: 25878777 PMCID: PMC4379333 DOI: 10.1093/ckj/sfu074] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Accepted: 06/24/2014] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Fibroblast Growth Factor-23 (FGF23) and cofactor Klotho are key regulators of mineral metabolism in chronic kidney disease (CKD), but little is known about the mechanisms that regulate their production. This study evaluates longitudinal changes of FGF23 and Klotho levels and their regulatory factors in children on chronic peritoneal dialysis (PD). METHODS FGF23, Klotho, 25(OH) vitamin D, 1,25-dihydroxyvitamin D and parathyroid hormone (PTH) plasma concentrations were measured during 1 year of follow-up in PD children. Anthropometric and dialytical parameters were evaluated in addition to mineral metabolism variables. RESULTS Thirty-one patients under chronic PD were followed for 12 months. FGF23 mean plasma levels at Month 1 were significantly increased compared with controls, 215.1 ± 303.6 versus 9.4 ± 5.7 pg/mL, respectively (P < 0.001). Baseline Klotho levels were 41% lower in patients compared with controls, 132.1 ± 58 versus 320 ± 119.4 pg/mL, respectively (P < 0.001), and did not correlate with FGF23 and phosphorus levels. At Month 12, FGF23 (195 ± 300 pg/mL) and Klotho levels (130 ± 34 pg/mL) remained similar to baseline values. Log-FGF23 correlated significantly with height/age Z score (r= -0.38) and residual renal function (r = -0.44), but no correlation was found with serum phosphorus, phosphate intake, PTH and vitamin D levels. The log-FGF23 strongly correlated with calcium levels at Months 1, 6 and 12, however, this relationship was blunted if serum phosphorus was >6 mg/dL. By multiple regression analysis, calcium was the strongest variable determining FGF23 levels. CONCLUSIONS In this longitudinal study, FGF23 levels are markedly increased, and Klotho levels are reduced in PD children compared with controls. FGF23 levels appeared to be regulated primarily by serum calcium, showing a significant correlation at each time of measurement. This relationship was lost in patients with phosphorus >6 mg/dL. These observations may have important consequences to the therapeutic management of phosphate homeostasis in CKD patients.
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Affiliation(s)
- Francisco J Cano
- Division of Pediatric Nephrology , Luis Calvo Mackenna Children's Hospital, Faculty of Medicine, University of Chile , Santiago , Chile
| | - Michael Freundlich
- Division of Pediatric Nephrology , University of Miami Miller School of Medicine , Miami, FL , USA
| | - Maria L Ceballos
- Division of Pediatric Nephrology , Luis Calvo Mackenna Children's Hospital, Faculty of Medicine, University of Chile , Santiago , Chile
| | - Angelica P Rojo
- Division of Pediatric Nephrology , Luis Calvo Mackenna Children's Hospital, Faculty of Medicine, University of Chile , Santiago , Chile
| | - Marta A Azocar
- Division of Pediatric Nephrology , Luis Calvo Mackenna Children's Hospital, Faculty of Medicine, University of Chile , Santiago , Chile
| | - Iris O Delgado
- Department of Biostatistics , Desarrollo University , Santiago , Chile
| | - Maria J Ibacache
- Division of Pediatric Nephrology , Luis Calvo Mackenna Children's Hospital, Faculty of Medicine, University of Chile , Santiago , Chile
| | - Maria A Delucchi
- Division of Pediatric Nephrology , Luis Calvo Mackenna Children's Hospital, Faculty of Medicine, University of Chile , Santiago , Chile
| | - Ana M Lillo
- Division of Pediatric Nephrology , Luis Calvo Mackenna Children's Hospital, Faculty of Medicine, University of Chile , Santiago , Chile
| | - Carlos E Irarrázabal
- Department of Pediatric Endocrinology , Molecular Physiology Laboratory, Faculty of Medicine, Los Andes University , Santiago , Chile
| | - Maria F Ugarte
- Department of Pediatric Endocrinology , Molecular Physiology Laboratory, Faculty of Medicine, Los Andes University , Santiago , Chile
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Abstract
PURPOSE OF REVIEW Disturbances in calcium-phosphate homeostasis play an important role in children with chronic kidney disease, and not only cause renal osteodystrophy but also result in increased cardiovascular morbidity and mortality. This review outlines the current aspects in the pathogenesis, diagnostic approach and treatment of renal osteodystrophy. RECENT FINDINGS The pathogenesis of renal osteodystrophy is under strong influence of the fibroblast growth factor 23/Klotho system, which is able to enhance phosphate excretion and reduce calcitriol synthesis in the kidney. Fibroblast growth factor 23 increases tissue calcinosis and is cardiotoxic, and is independently associated with mortality. Despite improvement in diagnostic imaging (bone density measurements), determination of biomarkers, mainly parathyroid hormone, still plays a central role. New treatment options resulted in improved bone health and also a reduction in mortality was achieved in adults with calcium-free phosphate binders. Substitution of active and inactive vitamin D is important and also has a beneficial effect on proteinuria. SUMMARY Knowledge about the biochemical and molecular mechanisms of renal osteodystrophy is increasing dramatically and has an impact not only to bone health but also overall morbidity and mortality. This will ultimately translate into further improved diagnostic approaches and novel treatment options.
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Immune, metabolic and epidemiological aspects of vitamin D in chronic kidney disease and transplant patients. Clin Biochem 2014; 47:509-15. [PMID: 24412344 DOI: 10.1016/j.clinbiochem.2013.12.026] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Revised: 12/27/2013] [Accepted: 12/28/2013] [Indexed: 12/19/2022]
Abstract
Chronic kidney disease strongly impacts on mineral and bone metabolism. Despite numerous medications, the biological targets recommended by international guidelines are often unmet. Among the treatment armamentarium, native or nutritional vitamin D (25OHD3) has been rediscovered in the early 2000s, and its general and specific actions further studied. Effects on bone, immunity, infection prevention, muscle function and phosphocalcic metabolism have been reviewed. Assessment of nutritional vitamin D status showed very low serum 25OHD3 levels and increase in nutritional vitamin D prescription led to improvement in these levels. However, about 45% of adult CKD patients still have insufficient serum 25OHD3 levels. Epidemiological studies should be enforced to describe further the mineral and bone disease management in CKD.
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Garland JS, Holden RM, Ross R, Adams MA, Nolan RL, Hopman WM, Morton AR. Insulin resistance is associated with Fibroblast Growth Factor-23 in stage 3-5 chronic kidney disease patients. J Diabetes Complications 2014; 28:61-5. [PMID: 24125760 DOI: 10.1016/j.jdiacomp.2013.09.004] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2013] [Revised: 08/30/2013] [Accepted: 09/10/2013] [Indexed: 11/29/2022]
Abstract
AIM To determine the associations between insulin resistance, fibroblast growth factor 23 (FGF-23), and coronary artery calcification (CAC) in chronic kidney disease (CKD) patients. INTRODUCTION FGF-23 is associated with atherosclerosis and cardiovascular disease, but its association with insulin resistance in CKD has not been explored. SUBJECTS Cross sectional study of 72 stage 3-5 CKD patients receiving care in Ontario, Canada. MATERIALS AND METHODS Insulin resistance was measured by the homeostasis model assessment of insulin resistance (HOMA-IR), FGF-23 was measured by carboxyl terminal enzyme linked immunoassay (ctFGF-23) and CAC was measured by multi-slice computed tomography. RESULTS Median HOMA-IR was 2.19μU/ml (interquartile range 1.19 to 3.94). Patients with HOMA-IR>2.2 had greater ctFGF-23 (179.7 vs 109.6; P=0.03), and 40% higher log CAC scores (2.09±0.87 vs 1.58±1.26; P=0.049). Multivariable linear regression adjusted for 1,25 dihydroxyvitamin D, kidney function, and parathyroid hormone revealed insulin resistance was a risk factor for greater log ctFGF-23 levels (log HOMA IR β=0.37; 95% confidence interval 0.14 to 0.59; P=0.002). CONCLUSIONS Insulin resistant CKD patients demonstrated higher FGF-23 levels, and increased CAC, while PO4 levels remained normal, suggesting a potential link between insulin resistance and PO4 homeostasis in CKD.
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Affiliation(s)
- Jocelyn S Garland
- Department of Medicine, Queen's University, Kingston, ON, Canada; Queen's University Vascular Calcification Investigators, Queen's University, Kingston, ON, Canada.
| | - Rachel M Holden
- Department of Medicine, Queen's University, Kingston, ON, Canada; Queen's University Vascular Calcification Investigators, Queen's University, Kingston, ON, Canada
| | - Robert Ross
- School of Kinesiology and Health Studies, Departments of Endocrinology and Metabolism, Queen's University, Kingston, ON, Canada
| | - Michael A Adams
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
| | - Robert L Nolan
- Queen's University Vascular Calcification Investigators, Queen's University, Kingston, ON, Canada; Department of Radiology, Queen's University, Kingston, ON, Canada
| | - Wilma M Hopman
- Queen's University Vascular Calcification Investigators, Queen's University, Kingston, ON, Canada; Clinical Research Center, Kingston General Hospital, and Department of Community Health and Epidemiology, Queen's University, Kingston, Ontario, Canada
| | - A Ross Morton
- Department of Medicine, Queen's University, Kingston, ON, Canada; Queen's University Vascular Calcification Investigators, Queen's University, Kingston, ON, Canada
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