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Chen H, Segev G, Mazaki‐Tovi M. Effects of Paricalcitol on Renal Secondary Hyperparathyroidism and Proteinuria in Dogs With Chronic Kidney Disease. J Vet Intern Med 2025; 39:e70063. [PMID: 40110605 PMCID: PMC11923454 DOI: 10.1111/jvim.70063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 02/27/2025] [Accepted: 03/04/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Renal secondary hyperparathyroidism (RHPT) is an inevitable consequence of chronic kidney disease (CKD). Paricalcitol might safely attenuate RHPT and proteinuria. HYPOTHESIS/OBJECTIVE Paricalcitol decreases parathyroid hormone (PTH) and proteinuria in dogs with CKD. ANIMALS Thirteen dogs with naturally acquired CKD. METHODS Placebo-controlled clinical trial. Dogs were randomly allocated to receive a placebo or paricalcitol (14 ng/kg/day) in a crossover design of 2, 12-week arms. Dogs were evaluated every 3 weeks. Associations between treatment, visit, and the outcome variables were assessed using generalized estimating equations. RESULTS PTH decreased by 22% (95% CI, 7%-35%, p = 0.006) in the paricalcitol-treated dogs and increased by 18% (95% CI, 2%-37%, p = 0.022) in the placebo-treated dogs with each visit. FGF-23 at 12 weeks increased compared with baseline in the paricalcitol-treated (mean 6941 pg/mL, 95% CI, 1781-20 057 vs. 489 pg/mL, 95% CI, 188-1272, p < 0.001, respectively), but not in the placebo-treated dogs (696 pg/mL, 95% CI, 316-1531 vs. 955 pg/mL, 95% CI, 308-2963, p = 0.529). Urine protein-to-creatinine ratio at 12 weeks increased compared with baseline in the placebo-treated (0.8, 95% CI, 0.3-1.3 vs. 0.5, 95% CI, 0.2-0.9, p = 0.04, respectively), but not in the paricalcitol-treated dogs (0.6, 95% CI, 0.3-0.9 vs. 1.0, 95% CI, 0.1-1.8, p = 0.35). Ionized calcium was unchanged between baseline and 12 weeks in the paricalcitol- and placebo-treated groups (1.3 mmol/L, 95% CI, 1.29-1.35 and 1.34, 95% CI, 1.27-1.40 vs. 1.30, 95% CI, 1.25-1.35, p = 0.12 and 1.28, 95% CI, 1.24-1.32, p = 0.034, respectively). However, 7/13 dogs developed mild hypercalcemia. Adverse effects were not reported by the owners. CONCLUSION AND CLINICAL IMPORTANCE Paricalcitol attenuated RHPT and stabilized renal proteinuria in dogs with CKD.
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Affiliation(s)
- Hilla Chen
- Department of Small Animal Internal Medicine, Koret School of Veterinary MedicineThe Hebrew University of JerusalemRehovotIsrael
| | - Gilad Segev
- Department of Small Animal Internal Medicine, Koret School of Veterinary MedicineThe Hebrew University of JerusalemRehovotIsrael
| | - Michal Mazaki‐Tovi
- Department of Small Animal Internal Medicine, Koret School of Veterinary MedicineThe Hebrew University of JerusalemRehovotIsrael
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Freitas P, Pereira L. Etelcalcetide: What we know eight years since its approval. Nefrologia 2025; 45:116-134. [PMID: 39986712 DOI: 10.1016/j.nefroe.2025.01.010] [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: 04/09/2024] [Accepted: 09/22/2024] [Indexed: 02/24/2025] Open
Abstract
INTRODUCTION AND OBJECTIVES The impact of etelcalcetide on patients with chronic kidney disease (CKD) and secondary hyperparathyroidism (SHPT) has been studied since its introduction in 2016/2017. However, only a handful of studies reported clinically relevant outcomes. This narrative review aims to summarize the published data about etelcalcetide, focusing on biochemical, cardiovascular (CV) and bone endpoints, as well as adverse effects and all-cause mortality. MATERIALS AND METHODS A literature review of the use of etelcalcetide in hemodialysis patients with SHPT was conducted. Several sources were used, such as PubMed, Google Scholar and Cochrane Library. RESULTS Regarding bone and mineral metabolism, etelcalcetide is effective in reducing serum levels of parathormone (PTH), calcium, phosphate and fibroblast growth factor 23 (FGF23). Preliminary data have highlighted its role in reducing bone turnover and improving mineralization and preservation of bone structure, indicating a possible positive impact on renal osteodystrophy. From a CV perspective, etelcalcetide is associated with a significant reduction in left ventricular hypertrophy. In addition, etelcalcetide reduces FGF23 and increases sclerostin serum levels. This data suggests a possible CV beneficial effect. CONCLUSIONS Etelcalcetide is effective in controlling SHPT. Promising data is available for some bone and surrogate cardiovascular endpoints, suggesting a possible beneficial effect. There is a lack of studies specifically designed to evaluate its role in reducing fractures, CV and all-cause mortality.
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Affiliation(s)
- Pedro Freitas
- Faculty of Medicine, Oporto University, Alameda Prof. Hernâni Monteiro, Porto, Portugal.
| | - Luciano Pereira
- Department of Medicine, Faculty of Medicine, Oporto University, Alameda Prof. Hernâni Monteiro, Porto, Portugal
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Donate-Correa J, Martín-Núñez E, Hernández-Carballo C, González-Luis A, Mora-Fernández C, Martín-Olivera A, Rodríguez-Ramos S, Cerro-López P, López-Castillo Á, Delgado-Molinos A, López-Tarruella VC, Navarro-González JF. FGF23 as a Potential Pathophysiological Factor in Peripheral Arterial Disease Associated with Chronic Kidney Disease. Int J Mol Sci 2024; 25:5457. [PMID: 38791495 PMCID: PMC11121420 DOI: 10.3390/ijms25105457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 05/15/2024] [Accepted: 05/16/2024] [Indexed: 05/26/2024] Open
Abstract
Fibroblast growth factor 23 (FGF23) levels are often elevated in chronic kidney disease (CKD). FGF23 and inflammation are common characteristics in CKD, and both are associated with worse disease progression and the occurrence of complications. The existence of an interaction between FGF23 and inflammation has been suggested, each of which influences the expression and activity of the other, leading to a vicious feedback loop with adverse outcomes, including cardiovascular disease and mortality. In this work, we determined circulating FGF23 levels in a group of patients with CKD stages 3 and 4 subjected to elective femoral endarterectomy due to established peripheral artery disease (PAD), a condition resulting from an athero-inflammatory process, and we studied its associations with different inflammatory markers and mediators. We evaluated its association with serum tumor necrosis factor (TNF)α, interleukin (IL) 6, and IL10, as well as with the gene expression levels of these parameters and A disintegrin and metalloproteinase domain-containing protein (ADAM) 17 in femoral vascular tissue and peripheral blood circulating cells (PBCCs). We also analyzed its association with serum concentrations of C-reactive protein (CRP), the systemic immune inflammation index (SII), and the neutrophil-to-lymphocyte ratio (NLR). Finally, we determined the vascular immunoreactivity of protein TNFα in a subgroup of patients. FGF23 concentrations were independently associated with circulating and PBCC mRNA levels of TNFα. Worst kidney function and diabetes were also found to be contributing to FGF23 levels. Patients with higher levels of FGF23 also had greater vascular immunoreactivity for TNFα.
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Affiliation(s)
- Javier Donate-Correa
- Research Unit, University Hospital Nuestra Señora de Candelaria (UHNSC), 38010 Santa Cruz de Tenerife, Spain; (E.M.-N.); (C.H.-C.); (A.G.-L.); (C.M.-F.); (A.M.-O.)
- GEENDIAB (Grupo Español Para el Estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39000 Santander, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, 38000 Santa Cruz de Tenerife, Spain
- RICORS2040 (RD21/0005/0013), Instituto de Salud Carlos III, 28000 Madrid, Spain
| | - Ernesto Martín-Núñez
- Research Unit, University Hospital Nuestra Señora de Candelaria (UHNSC), 38010 Santa Cruz de Tenerife, Spain; (E.M.-N.); (C.H.-C.); (A.G.-L.); (C.M.-F.); (A.M.-O.)
- Navarrabiomed (Miguel Servet Foundation), Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), 31008 Pamplona, Spain
| | - Carolina Hernández-Carballo
- Research Unit, University Hospital Nuestra Señora de Candelaria (UHNSC), 38010 Santa Cruz de Tenerife, Spain; (E.M.-N.); (C.H.-C.); (A.G.-L.); (C.M.-F.); (A.M.-O.)
| | - Ainhoa González-Luis
- Research Unit, University Hospital Nuestra Señora de Candelaria (UHNSC), 38010 Santa Cruz de Tenerife, Spain; (E.M.-N.); (C.H.-C.); (A.G.-L.); (C.M.-F.); (A.M.-O.)
- Doctoral and Graduate School, University of La Laguna, 38200 San Cristóbal de La Laguna, Spain
| | - Carmen Mora-Fernández
- Research Unit, University Hospital Nuestra Señora de Candelaria (UHNSC), 38010 Santa Cruz de Tenerife, Spain; (E.M.-N.); (C.H.-C.); (A.G.-L.); (C.M.-F.); (A.M.-O.)
- GEENDIAB (Grupo Español Para el Estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39000 Santander, Spain
- RICORS2040 (RD21/0005/0013), Instituto de Salud Carlos III, 28000 Madrid, Spain
| | - Alberto Martín-Olivera
- Research Unit, University Hospital Nuestra Señora de Candelaria (UHNSC), 38010 Santa Cruz de Tenerife, Spain; (E.M.-N.); (C.H.-C.); (A.G.-L.); (C.M.-F.); (A.M.-O.)
| | - Sergio Rodríguez-Ramos
- Transplant Coordination, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (S.R.-R.); (P.C.-L.)
| | - Purificación Cerro-López
- Transplant Coordination, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (S.R.-R.); (P.C.-L.)
| | - Ángel López-Castillo
- Vascular Surgery Service, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (Á.L.-C.); (A.D.-M.)
| | - Alejandro Delgado-Molinos
- Vascular Surgery Service, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; (Á.L.-C.); (A.D.-M.)
| | | | - Juan F. Navarro-González
- Research Unit, University Hospital Nuestra Señora de Candelaria (UHNSC), 38010 Santa Cruz de Tenerife, Spain; (E.M.-N.); (C.H.-C.); (A.G.-L.); (C.M.-F.); (A.M.-O.)
- GEENDIAB (Grupo Español Para el Estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39000 Santander, Spain
- Instituto de Tecnologías Biomédicas, Universidad de La Laguna, 38000 Santa Cruz de Tenerife, Spain
- RICORS2040 (RD21/0005/0013), Instituto de Salud Carlos III, 28000 Madrid, Spain
- Nephrology Service, University Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
- Facultad de Ciencias de la Salud, Universidad Fernando Pessoa Canarias, 35450 Las Palmas de Gran Canaria, Spain
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Bouzemane A, Vignot E, Derain Dubourg L, De Mul A, Molin A, Chapurlat R, Fontanges E, Delsart D, Akbari A, Huang SHS, McIntyre CW, Bacchetta J, Lemoine S. Reassuring Data on the Cardiovascular Risk in Adults With X-linked Hypophosphatemia Receiving Conventional Therapy. J Clin Endocrinol Metab 2024; 109:e488-e494. [PMID: 37843399 DOI: 10.1210/clinem/dgad608] [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: 07/09/2023] [Revised: 09/04/2023] [Accepted: 10/11/2023] [Indexed: 10/17/2023]
Abstract
CONTEXT X-linked hypophosphatemia (XLH) is a rare genetic disorder that results in increased plasma levels of fibroblast growth factor 23 (FGF23). Several studies have demonstrated a direct association between FGF23 and cardiovascular mortality in cohorts of patients with chronic renal failure. However, in patients with XLH, studies on the cardiovascular impact of the disease are rare, with contradictory results. OBJECTIVE The aim was to assess whether the disease led to an increased cardiovascular risk. METHODS We conducted a single-center retrospective observational study on a local cohort of adult patients with XLH. The primary endpoint was a composite endpoint of the frequency of left ventricular hypertrophy (LVH) or presence of high blood pressure. Our secondary objectives were to assess echocardiographic, pulse wave velocity, and central blood pressure data as other markers of CV health. Independently of this cohort, tissue sodium content with magnetic resonance imaging was studied in 2 patients with XLH before and after burosumab. RESULTS Twenty-two patients were included. Median serum phosphate was 0.57 (0.47-0.72) mmol/L and FGF23 94 pg/L (58-2226). Median blood pressure was 124 (115-130)/68 (65-80) mm Hg, with only 9% of patients being hypertensive. A majority of patients (69%) had no LVH, only 1 had a left ventricular mass >100 g/m² and 25% of patients had left ventricular remodeling. Pulse wave velocity was normal in all patients. No differences in skin and muscle sodium content were observed before and after burosumab in the 2 patients who underwent sodium magnetic resonance imaging. CONCLUSION We found no elevated risk of developing hypertension or LVH in patients with XLH.
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Affiliation(s)
- Alexandre Bouzemane
- Hospices Civils de Lyon, Nephrology, hypertension renal and functional exploration, Hôpital Edouard Herriot, 69003, Lyon, France
| | | | - Laurence Derain Dubourg
- Hospices Civils de Lyon, Nephrology, hypertension renal and functional exploration, Hôpital Edouard Herriot, 69003, Lyon, France
| | - Aurélie De Mul
- Reference centre for rare calcium and phosphorus diseases, paediatric rheumatology and dermatology, rare diseases network, OSCAR, ORKID, ERKNet BOND, HFME, Bron 69029, France
| | - Arnaud Molin
- Genetic department, Centre Hospitalier Universitaire de Caen, Caen, 14033, France
| | - Roland Chapurlat
- Rheumatology Department, CHU Edouard-Herriot, 69003 Lyon, France
| | | | - Daphne Delsart
- Cardiology functional explorations, Hopital Edouard-Herriot, 69003 Lyon, France
| | - Alireza Akbari
- Canada Kidney clinical research unit, London Health Sciences Centre, East London, ON, N6A 5W9Canada
| | - Shih Han Susan Huang
- Canada Kidney clinical research unit, London Health Sciences Centre, East London, ON, N6A 5W9Canada
| | - Christopher W McIntyre
- Canada Kidney clinical research unit, London Health Sciences Centre, East London, ON, N6A 5W9Canada
| | - Justine Bacchetta
- Reference centre for rare calcium and phosphorus diseases, paediatric rheumatology and dermatology, rare diseases network, OSCAR, ORKID, ERKNet BOND, HFME, Bron 69029, France
- University of Lyon, CarMeN Laboratory, IRIS Team, INSERM, INSERM1033, INRA, INSA Lyon, 69100, Villeurbanne, France
- INSERM 1033, prevention of bone diseases, 69008 Lyon, France
| | - Sandrine Lemoine
- Hospices Civils de Lyon, Nephrology, hypertension renal and functional exploration, Hôpital Edouard Herriot, 69003, Lyon, France
- Reference centre for rare calcium and phosphorus diseases, paediatric rheumatology and dermatology, rare diseases network, OSCAR, ORKID, ERKNet BOND, HFME, Bron 69029, France
- University of Lyon, CarMeN Laboratory, IRIS Team, INSERM, INSERM1033, INRA, INSA Lyon, 69100, Villeurbanne, France
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Junho CVC, Frisch J, Soppert J, Wollenhaupt J, Noels H. Cardiomyopathy in chronic kidney disease: clinical features, biomarkers and the contribution of murine models in understanding pathophysiology. Clin Kidney J 2023; 16:1786-1803. [PMID: 37915935 PMCID: PMC10616472 DOI: 10.1093/ckj/sfad085] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Indexed: 11/03/2023] Open
Abstract
The cardiorenal syndrome (CRS) is described as a multi-organ disease encompassing bidirectionally heart and kidney. In CRS type 4, chronic kidney disease (CKD) leads to cardiac injury. Different pathological mechanisms have been identified to contribute to the establishment of CKD-induced cardiomyopathy, including a neurohormonal dysregulation, disturbances in the mineral metabolism and an accumulation of uremic toxins, playing an important role in the development of inflammation and oxidative stress. Combined, this leads to cardiac dysfunction and cardiac pathophysiological and morphological changes, like left ventricular hypertrophy, myocardial fibrosis and cardiac electrical changes. Given that around 80% of dialysis patients suffer from uremic cardiomyopathy, the study of cardiac outcomes in CKD is clinically highly relevant. The present review summarizes clinical features and biomarkers of CKD-induced cardiomyopathy and discusses underlying pathophysiological mechanisms recently uncovered in the literature. It discloses how animal models have contributed to the understanding of pathological kidney-heart crosstalk, but also provides insights into the variability in observed effects of CKD on the heart in different CKD mouse models, covering both "single hit" as well as "multifactorial hit" models. Overall, this review aims to support research progress in the field of CKD-induced cardiomyopathy.
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Affiliation(s)
| | - Janina Frisch
- Department of Biophysics, Center for Integrative Physiology and Molecular Medicine, Medical Faculty, Saarland University, Center for Human and Molecular Biology, Homburg/Saar, Germany
| | - Josefin Soppert
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
- Department of Anesthesiology, University Hospital RWTH Aachen, Aachen, Germany
| | - Julia Wollenhaupt
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
| | - Heidi Noels
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
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Ozdemir N, Toraman A, Taneli F, Yurekli BS, Hekimsoy Z. An evaluation of both serum Klotho/FGF-23 and apelin-13 for detection of diabetic nephropathy. Hormones (Athens) 2023; 22:413-423. [PMID: 37458962 DOI: 10.1007/s42000-023-00464-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 06/26/2023] [Indexed: 08/25/2023]
Abstract
PURPOSE The aim of our study is to evaluate whether serum Klotho/FGF-23 and apelin-13 can be used as new biomarkers for detection of development of nephropathy. METHODS In this cross-sectional study, 88 type 2 diabetes mellitus (T2DM) patients and 38 healthy controls were included. The mean duration of T2DM was 11.4 ± 9.7 years. T2DM individuals were categorized into two groups as group 1 with e-GFR < 60 mL/min/1.73 m2 and group 2 with e-GFR > 60 mL/min/1.73 m2. They were also divided into two groups according to their 24 h urine albumin levels, classifying them as follows: normoalbuminuria if less than 30 mg/day and albuminuria if more than 30 mg/day. RESULTS Mean serum Klotho levels in the T2DM group were observed to be significantly higher than in the control group. Serum apelin-13 levels were observed to be significantly lower in the T2DM group compared to the control group (p < 0.001). In the diabetic group, apelin-13 levels were positively correlated with age, waist circumference, and albuminuria while they were negatively correlated with e-GFR. Apelin-13 levels were seen to be significantly higher in group 1 (p < 0.001). CONCLUSION Apelin-13 levels were found to be significantly higher in individuals with diabetic nephropathy than in those without diabetic nephropathy. In the diabetic group, a significant relationship was detected between apelin-13 levels and albumin excretion. Based on these findings, we consider that serum Klotho and apelin-13 levels may have a protective effect on diabetic nephropathy and can additionally be used as a biomarker to predict diabetic nephropathy.
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Affiliation(s)
- Nilufer Ozdemir
- Department of Endocrinology and Metabolism, Faculty of Medicine, Manisa Celal Bayar University, Manisa, Turkey.
| | - Aysun Toraman
- Department of Nephrology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, Turkey
| | - Fatma Taneli
- Department of Clinical Biochemistry, Faculty of Medicine, Manisa Celal Bayar University, Manisa, Turkey
| | - Banu Sarer Yurekli
- Department of Endocrinology and Metabolism, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Zeliha Hekimsoy
- Department of Endocrinology and Metabolism, Faculty of Medicine, Manisa Celal Bayar University, Manisa, Turkey
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Ramos P, Larson B, Ashrafzadeh-Kian S, Ito N, Kato H, Bornhorst JA, Algeciras-Schimnich A. Intact Fibroblast Growth Factor 23 Concentrations in Hypophosphatemic Disorders. Endocr Pract 2023; 29:193-198. [PMID: 36627024 DOI: 10.1016/j.eprac.2023.01.003] [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: 10/26/2022] [Revised: 12/23/2022] [Accepted: 01/03/2023] [Indexed: 01/08/2023]
Abstract
OBJECTIVE Evaluation of circulating fibroblast growth factor 23 (FGF23) concentrations plays a key role in the differential diagnosis of patients presenting with hypophosphatemia. FGF23 concentrations obtained by different immunoassays are not comparable and subsequently, differences in the clinical performance of the assays might arise. In this study, we evaluated the clinical performance of the Medfrontier FGF23 Intact immunoassay (MedFrontier, Minaris Medical Co, Ltd, Tokyo, Japan) in clinically relevant hypophosphatemic conditions. METHODS Intact FGF23 (iFGF23) was measured in serum samples from 61 patients with FGF23-dependent hypophosphatemia (42-tumor induced osteomalacia [TIO] and 19-X-linked hypophosphatemia [XLH]); 8 patients with FGF23-independent hypophosphatemia (6-Fanconi Syndrome and 2-Vitamin D dependent rickets); 10 normophosphatemic patients; 15 chronic kidney disease (CKD) stage-2/3 and 20 CKD stage-4/5 patients; and a healthy control population. Disease-specific differences in measured iFGF23 concentrations and FGF23 concentration association with phosphate concentrations were reported. RESULTS iFGF23 concentrations were significantly elevated in 90% and 84% of TIO and XLH hypophosphatemia patients as compared to healthy controls (both TIO and XLH, P = .0001). There was no significant correlation between iFGF23 and phosphate concentrations (P = .74 and P = .86) for TIO and XLH, respectively. Patients with CKD showed a significant increase in serum iFGF23 as the estimated glomerular filtration rate decreased (ρ = -0.79, P ≤ 0.0001). CONCLUSIONS This study evaluated the clinical performance of the MedFrontier iFGF23 assay in a large cohort of XLH and TIO Caucasian and Asian patients. The clinical sensitivity of this iFGF23 assay is appropriate for clinical use.
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Affiliation(s)
- Paola Ramos
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Bethany Larson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | | | - Nobuaki Ito
- Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan; Osteoporosis Center, The University of Tokyo Hospital, Tokyo, Japan
| | - Hajime Kato
- Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan; Osteoporosis Center, The University of Tokyo Hospital, Tokyo, Japan
| | - Joshua A Bornhorst
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
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[Evolution of the incidence and results at 12 months of parathyroidectomy: 40 years of experience in a dialysis center with two successive surgical departments]. Nephrol Ther 2022; 18:616-626. [PMID: 36328900 DOI: 10.1016/j.nephro.2022.07.400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 05/18/2022] [Accepted: 07/19/2022] [Indexed: 11/06/2022]
Abstract
INTRODUCTION Secondary hyperparathyroidism remains the main complication of mineral and bone metabolism in patients with chronic kidney disease. In case of resistance to medical treatment (native and active vitamin D, calcium and calcimimetics), surgical parathyroidectomy is indicated. The aim of this retrospective study is to show the evolution of the incidence and results of surgical parathyroidectomy in our center between 1980 and 2020 as patient characteristics, diagnostic and therapeutic strategies have changed. PATIENTS AND METHODS We collected data from dialysis patients who had a first surgical parathyroidectomy between 2000 and 2020 (period 2) in the same surgical department and compared them with historical data between 1980 and 1999 (period 1) operated in one other center. RESULTS In period 1, 53 surgical parathyroidectomy were performed (2.78/year, 0 to 5, 8.5/1000 patients-year) vs.56 surgical parathyroidectomy in period 2 (2.8/year, 0 to 9, 8/1000 patients-year). The patients of the 2 periods were comparable except for the higher dialysis vintage in period 1 (149±170 vs.89±94 months; P=0.02). In comparison with dialysis patients not requiring surgical parathyroidectomy during the same period, patients who had surgical parathyroidectomy were younger, had higher dialysis vintage and lower diabetes prevalence, but more frequently carriers of glomerulopathy or polycystosis. Systematically performed in period 2, cervical ultrasound identified at least one visible gland in 78.6% of cases while the scintigraphy, performed only in 66% of cases, found at least one gland in 81% of cases. Twelve months after surgery, PTH > 300 pg/mL (marker of secondary hyperparathyroidism recurrence or surgery failure) was present in 30% of patients in period 1 vs. 5.3% in period 2. Hypoparathyroidism was also more frequently observed in period 2 (35.7 vs. 18.8%). Surgical complications were also higher in period 1. CONCLUSION Despite therapeutic and strategic advances, severe secondary hyperparathyroidism is still as common as ever. It is favored by excessively high PTH targets, by suboptimal prevention before dialysis and poor tolerance of calcimimetics. The surgical parathyroidectomy is effective and safe in the hands of a specialized team with an ultrasound and scintigraphic preoperative assessment.
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Li L, Gan H. Intact Fibroblast Growth Factor 23 Regulates Chronic Kidney Disease–Induced Myocardial Fibrosis by Activating the Sonic Hedgehog Signaling Pathway. J Am Heart Assoc 2022; 11:e026365. [DOI: 10.1161/jaha.122.026365] [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: 11/16/2022]
Abstract
Background
Clinically, myocardial fibrosis is one of the most common complications caused by chronic kidney disease (CKD). However, the potential mechanisms of CKD‐induced myocardial fibrosis have not been clarified.
Methods and Results
In our in vivo study, a rat model of CKD with 5/6 nephrectomy was established. The CKD model was treated with the glioma 1 (Gli‐1) inhibitor GANT‐61, and myocardial fibrosis and serum intact fibroblast growth factor 23 levels were assessed 16 weeks after nephrectomy. Finally, we found that Gli‐1 and Smoothened in the Sonic Hedgehog (Shh) signaling pathway were activated and that collagen‐1 and collagen‐3, which constitute the fibrotic index, were expressed in CKD myocardial tissue. After administering the Gli‐1 inhibitor GANT‐61, the degree of myocardial fibrosis was reduced, and Gli‐1 expression was also inhibited. We also measured blood pressure, cardiac biomarkers, and other indicators in rats and performed hematoxylin‐eosin staining of myocardial tissue. Furthermore, in vitro studies showed that intact fibroblast growth factor 23 promoted cardiac fibroblast proliferation and transdifferentiation into myofibroblasts by activating the Shh signaling pathway, thereby promoting cardiac fibrosis, as manifested by increased expression of the Shh, Patch 1, and Gli‐1 mRNAs and Shh, Smoothened, and Gli‐1 proteins in the Shh signaling pathway. The protein and mRNA levels of other fibrosis indicators, such as α‐smooth muscle actin, which are also markers of transdifferentiation, collagen‐1, and collagen‐3, were increased.
Conclusions
On the basis of these results, intact fibroblast growth factor 23 promotes CKD‐induced myocardial fibrosis by activating the Shh signaling pathway.
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Affiliation(s)
- Lanlan Li
- Department of Nephrology The First Affiliated Hospital of Chongqing Medical University Chongqing China
| | - Hua Gan
- Department of Nephrology The First Affiliated Hospital of Chongqing Medical University Chongqing China
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10
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Ammar YA, Maharem DA, Mohamed AH, Khalil GI, Shams-Eldin RS, Dwedar FI. Fibroblast growth factor-23 rs7955866 polymorphism and risk of chronic kidney disease. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2022. [DOI: 10.1186/s43042-022-00289-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
A missense gain-of-function fibroblast growth factor-23 (FGF23) gene single nucleotide polymorphism (SNP) (rs7955866) has been associated with FGF23 hypersecretion, phosphaturia, and bone disease. Excess circulating FGF23 was linked with atherosclerosis, hypertension, initiation, and progression of chronic kidney disease (CKD).
Methods
The study included 72 CKD stage 2/3 Egyptian patients (27–71 years old, 37 females) and 26 healthy controls matching in age and sex. Repeated measures of blood pressure were used to quantify hypertension on a semiquantitative scale (grades 0 to 5). Fasting serum urea, creatinine, uric acid, total proteins, albumin, calcium, phosphorus, vitamin D3, intact parathyroid hormone (iPTH), and intact FGF23 (iFGF23) were measured. DNA extracted from peripheral blood leucocytes was used for genotyping of FGF23 rs7955866 SNP using the TaqMan SNP genotyping allelic discrimination method.
Results
Major causes of CKD were hypertension, diabetic kidney disease, and CKD of unknown etiology. There was no significant difference in minor allele (A) frequency between the studied groups (0.333 in GI and 0.308 in GII). Median (IQR) serum iFGF23 was significantly higher in GI [729.2 (531.9–972.3)] than in GII [126.1 (88.5–152.4)] pg/mL, P < 0.001. Within GI, the minor allele (A) frequency load, coded for codominant inheritance, had a significant positive correlation with both hypertension grade (r = 0.385, P = 0.001) and serum iFGF23 (r = 0.259, P = 0.028). Hypertension grade had a significant positive correlation with serum phosphorus and iFGF23.
Conclusions
For the first time in an Egyptian cohort, we report a relatively high frequency of the rs7955866 SNP. It may remain dormant or become upregulated in response to some environmental triggers, notably dietary phosphorus excess, leading to increased circulating iFGF23 with ensuing hypertension and/or renal impairment. Subjects with this SNP, particularly in the homozygous form, are at increased risk for CKD of presumably “unknown” etiology, with a tendency for early onset hypertension and increased circulating iFGF23 out of proportion with the degree of renal impairment. Large-scale population studies are needed to confirm these findings and explore the role of blockers of the renin–angiotensin–aldosterone system and sodium chloride cotransporters in mitigating hypertension associated with FGF23 excess.
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11
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Association of Serum Creatinine Level with Prognosis of Laparotomy for Acute Mesenteric Ischemia after Cardiovascular Surgery. Surg Res Pract 2022; 2022:1737161. [PMID: 35386950 PMCID: PMC8979745 DOI: 10.1155/2022/1737161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 03/14/2022] [Indexed: 12/04/2022] Open
Abstract
Introduction Acute mesenteric ischemia is a life-threatening complication after cardiovascular surgery with a mortality rate of 52.9–81.3%. However, few studies have evaluated the predictors of clinical outcome after treatment for acute mesenteric ischemia following cardiovascular surgery. Therefore, this study aimed to elucidate prognostic factors in patients who underwent laparotomy for acute mesenteric ischemia after cardiovascular surgery. Methods We retrospectively analyzed 29 patients (20 men and 9 women; median age, 71.0 years) who underwent laparotomy for acute mesenteric ischemia after cardiovascular surgery between January 2010 and August 2020. These patients were classified into the survivor group (comprising patients who were discharged or referred to another hospital, n = 16) and the nonsurvivor group (comprising those who experienced in-hospital mortality, n = 13). We compared clinical parameters between the groups to identify the predictors of outcomes. Results More patients in the nonsurvivor group underwent emergency cardiovascular surgery (62.5% vs. 100%, p = 0.017) and received hemodialysis (12.5% vs. 61.5%, p = 0.008) at the onset of acute mesenteric ischemia than those in the survivor group. The prelaparotomy serum creatinine level was higher in the nonsurvivor group than in the survivor group (1.27 vs. 2.33 mg/dL, p = 0.004). Logistic regression analysis revealed an association between preoperative serum creatinine level and in-hospital mortality (odds ratio 5.047, p = 0.046), and Cox regression analysis demonstrated a relationship between serum creatinine level and in-hospital mortality (hazard ratio 1.610, p = 0.009). The area under the curve (receiver operating characteristic analysis) for the serum creatinine level was 0.813. Furthermore, the optimal cutoff value of the serum creatinine level was 1.59 mg/dL with a sensitivity and specificity of 0.846 and 0.687, respectively, in predicting in-hospital mortality. Conclusions The elevated serum creatinine level was associated with a poor clinical outcome after surgery for acute mesenteric ischemia following cardiovascular surgery.
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12
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Shigematsu T, Asada S, Endo Y, Kawata T, Fukagawa M, Akizawa T. Evocalcet with vitamin D receptor activator treatment for secondary hyperparathyroidism. PLoS One 2022; 17:e0262829. [PMID: 35176038 PMCID: PMC8853539 DOI: 10.1371/journal.pone.0262829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 12/28/2021] [Indexed: 11/18/2022] Open
Abstract
This ad hoc analysis of a previously conducted phase 3 head-to-head comparison study of evocalcet and cinacalcet in secondary hyperparathyroidism patients undergoing maintenance hemodialysis evaluated the efficacy and safety of combined once-daily oral evocalcet and intravenous vitamin D receptor activator treatment stratified by weekly vitamin D receptor activator dose (117, 45, and 91 patients in no, low [< 1.5 μg], and high [≥ 1.5 μg] dose groups, respectively). Effects of vitamin D receptor activator were assessed on the basis of intact parathyroid hormone, corrected calcium, phosphorus, and fibroblast growth factor-23 levels; percent changes from baseline; proportions of patients who achieved target intact parathyroid hormone, corrected calcium, and phosphorus at Weeks 28–30; and adverse drug reactions. Intact parathyroid hormone, corrected calcium, phosphorus, and fibroblast growth factor-23 levels decreased in all groups; phosphorus and fibroblast growth factor-23 levels remained high in the high dose group. In the low and high dose groups, greater proportions of patients achieved the corrected calcium target compared with the no dose group (p = 0.043). Ratios of intact-to-C-terminal fibroblast growth factor-23 decreased in all groups. In low and high dose groups, hypocalcemia was less common than in the no dose group (p = 0.014). Evocalcet with concomitant vitamin D receptor activator demonstrated benefits such that more patients achieved the corrected calcium target and exhibited decreased fibroblast growth factor-23 synthesis; the incidence of hypocalcemia also decreased.
Clinical trial registration: ClinicalTrials.gov (NCT02549391) and JAPIC (JapicCTI-153013).
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Affiliation(s)
- Takashi Shigematsu
- Department of Nephrology, Wakayama Medical University, Wakayama, Japan
- * E-mail:
| | - Shinji Asada
- Medical Affairs Department, Kyowa Kirin Co., Ltd., Tokyo, Japan
| | - Yuichi Endo
- R&D Division, Kyowa Kirin Co., Ltd., Tokyo, Japan
| | - Takehisa Kawata
- Medical Affairs Department, Kyowa Kirin Co., Ltd., Tokyo, Japan
| | - Masafumi Fukagawa
- Division of Nephrology, Endocrinology, and Metabolism, Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan
| | - Tadao Akizawa
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
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Leifheit-Nestler M, Vogt I, Haffner D, Richter B. Phosphate Is a Cardiovascular Toxin. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1362:107-134. [DOI: 10.1007/978-3-030-91623-7_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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14
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Fibroblast Growth Factor 23 as Regulator of Vitamin D Metabolism. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1362:47-54. [DOI: 10.1007/978-3-030-91623-7_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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15
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Gembillo G, Visconti L, Giusti MA, Siligato R, Gallo A, Santoro D, Mattina A. Cardiorenal Syndrome: New Pathways and Novel Biomarkers. Biomolecules 2021; 11:1581. [PMID: 34827580 PMCID: PMC8615764 DOI: 10.3390/biom11111581] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/22/2021] [Accepted: 10/22/2021] [Indexed: 12/15/2022] Open
Abstract
Cardiorenal syndrome (CRS) is a multi-organ disease characterized by the complex interaction between heart and kidney during acute or chronic injury. The pathogenesis of CRS involves metabolic, hemodynamic, neurohormonal, and inflammatory mechanisms, and atherosclerotic degeneration. In the process of better understanding the bi-directional pathophysiological aspects of CRS, the need to find precise and easy-to-use markers has also evolved. Based on the new pathophysiological standpoints and an overall vision of the CRS, the literature on renal, cardiac, metabolic, oxidative, and vascular circulating biomarkers was evaluated. Though the effectiveness of different extensively applied biomarkers remains controversial, evidence for several indicators, particularly when combined, has increased in recent years. From new aspects of classic biomarkers to microRNAs, this review aimed at a 360-degree analysis of the pathways that balance the kidney and the heart physiologies. In this delicate system, different markers and their combination can shed light on the diagnosis, risk, and prognosis of CRS.
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Affiliation(s)
- Guido Gembillo
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy;
- Department of Biomedical and Dental Sciences and Morpho-Functional Imaging, University of Messina, 98125 Messina, Italy
| | - Luca Visconti
- Unit of Nephrology and Dialysis, Ospedali Riuniti Villa Sofia Cervello, University of Palermo, 90146 Palermo, Italy;
| | - Maria Ausilia Giusti
- Diabetes and Islet Transplantation Unit, Department of Diagnostic and Therapeutic Services, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), UPMC Italy, 90127 Palermo, Italy; (M.A.G.); (A.M.)
| | - Rossella Siligato
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy;
- Department of Biomedical and Dental Sciences and Morpho-Functional Imaging, University of Messina, 98125 Messina, Italy
| | - Alessia Gallo
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), UPMC Italy, 90127 Palermo, Italy;
| | - Domenico Santoro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy;
| | - Alessandro Mattina
- Diabetes and Islet Transplantation Unit, Department of Diagnostic and Therapeutic Services, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), UPMC Italy, 90127 Palermo, Italy; (M.A.G.); (A.M.)
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16
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Mason DL, Godugu K, Nnani D, Mousa SA. Effects of sevelamer carbonate versus calcium acetate on vascular calcification, inflammation, and endothelial dysfunction in chronic kidney disease. Clin Transl Sci 2021; 15:353-360. [PMID: 34599865 PMCID: PMC8841464 DOI: 10.1111/cts.13151] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/28/2021] [Accepted: 08/03/2021] [Indexed: 01/12/2023] Open
Abstract
Hyperphosphatemia is present in most patients with end‐stage renal disease (ESRD) and has been associated with increased cardiovascular mortality. Phosphate binders (calcium‐based and calcium free) are the mainstay pharmacologic treatment to lower phosphorus levels in patients with ESRD. We evaluated biochemical markers of vascular calcification, inflammation, and endothelial dysfunction in patients with chronic kidney disease (CKD) treated with sevelamer carbonate (SC) versus calcium acetate (CA). Fifty patients with CKD (stages 3 and 4) were enrolled and assigned to treatment with SC and CA for 12 weeks. At the end of the study the biomarkers of vascular calcification, inflammation, and endothelial dysfunction were analyzed. A significant increase in HDL‐cholesterol was observed with SC but not with CA in patients with CKD. Treatment with SC reduced serum phosphate, calcium phosphate, and FGF‐23 levels and there was no change with CA treatment. The inflammatory markers IL‐8, IFN‐γ, and TNFα decreased with response to both treatments. The levels of IL‐6 significantly increased with CA treatment and no change was observed in the SC treatment group. SC showed favorable effects on anti‐inflammatory and vascular calcification biomarkers compared to CA treatment in patients with CKD stages 3 and 4 with normal phosphorous values.
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Affiliation(s)
- Darius L Mason
- Methodist Le Bonheur Healthcare, Memphis, Tennessee, USA.,Department of Clinical Pharmacy & Translational Science, The University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Kavitha Godugu
- The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, New York, USA
| | - Daryl Nnani
- Department of Pharmacy, Montefiore Medical Center, The University Hospital for Albert Einstein College of Medicine, Bronx, New York, USA
| | - Shaker A Mousa
- The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, New York, USA
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17
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Roy N, Rosas SE. IL-6 Is Associated with Progression of Coronary Artery Calcification and Mortality in Incident Dialysis Patients. Am J Nephrol 2021; 52:745-752. [PMID: 34535589 DOI: 10.1159/000518652] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 07/20/2021] [Indexed: 01/07/2023]
Abstract
INTRODUCTION Inflammation is important in the pathogenesis of atherosclerosis. Elevated interleukin-6 (IL-6) is associated with cardiovascular events and also predicts mortality in individuals with CKD. Our goal was to determine the association between IL-6, FGF23, and high-sensitivity C-reactive protein (hsCRP) on coronary artery calcification (CAC) progression and mortality in incident dialysis patients without prior coronary events. METHODS A prospective cohort of incident adult dialysis participants had CAC measured by ECG-triggered multislice CT scans at baseline and at least 12 months later. Lipids, mineral metabolism markers, FGF23, and inflammatory markers, such as IL-6 and hsCRP, were measured at the baseline visit. RESULTS Participants in the high IL-6 tertile had the highest baseline CAC score (133.25 [10.35-466.15]) compared to the low (0.25 [0-212.2]) and intermediate (29.55 [0-182.85]) tertiles. Almost half of the participants with high IL-6 (15 of 32 [46.9%]) experienced progression of CAC compared to participants with low (8 of 32 [25%]) and intermediate (9 of 32 [28.1%]) (p = 0.05) IL-6 levels. Each log increase in IL-6 was associated with increase in death (hazard ratio 2.2, 95% CI: 1.2-3.8; p = 0.01). After adjusting for smoking, age, gender, race, diabetes, phosphate, and baseline calcium score, IL-6 (log) was associated with 2.2 times (95% CI: 1.1-4.6; p = 0.03) increase in death. CONCLUSION IL-6 is associated with progression of CAC and mortality in incident dialysis patients.
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Affiliation(s)
- Neil Roy
- Kidney and Hypertension Unit, Joslin Diabetes Center, Boston, Massachusetts, USA,
- Harvard Medical School, Boston, Massachusetts, USA,
| | - Sylvia E Rosas
- Kidney and Hypertension Unit, Joslin Diabetes Center, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
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18
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Cornelissen A, Florescu R, Kneizeh K, Cornelissen C, Brandenburg V, Liehn E, Schuh A. Intact fibroblast growth factor 23 levels and outcome prediction in patients with acute heart failure. Sci Rep 2021; 11:15507. [PMID: 34330955 PMCID: PMC8324826 DOI: 10.1038/s41598-021-94780-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 07/09/2021] [Indexed: 12/13/2022] Open
Abstract
Elevated fibroblast growth factor 23 (FGF23) levels are associated with adverse outcome in populations with cardiovascular disease and chronic kidney failure. It is unclear if FGF23 has significance in prognosis estimation in patients with acute heart failure (HF) when compared to traditional risk estimation tools. Serum levels of intact FGF23 were assessed in 139 patients admitted to the Intermediate Care Unit of a tertiary hospital for acute HF. Patients were followed-up for one year. After exclusion of patients who were lost to follow-up, data outliers, and patients with sampling errors, the final study cohort comprised 133 patients. The Seattle Heart Failure (SHF) Model was used to estimate one-year survival. FGF23 levels correlated with HF severity and were strongly associated with one-year mortality. Associations between one-year outcome and FGF23, assessed on day 1 after admission, were still evident after multivariable adjustment (OR 15.07; 95%CI 1.75-129.79; p = 0.014). FGF23 levels predicted the one-year outcome with similar accuracy as the SHF Model, both if assessed on day 1 and on day 2 after admission (FGF23d1: AUC 0.784; 95%CI 0.669-0.899; FGF23d2: AUC 0.766; 95%CI 0.631-0.901; SHF: AUC 0.771; 95%CI 0.651-0.891). The assessment of FGF23 in patients with acute HF might help identify high-risk patients that are more prone to complications, need a closer follow-up and more aggressive treatment.
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Affiliation(s)
- Anne Cornelissen
- Department of Cardiology, Angiology and Internal Intensive Medicine, University Hospital Aachen, RWTH Aachen University, Aachen, Germany
| | - Roberta Florescu
- Department of Cardiology, Angiology and Internal Intensive Medicine, University Hospital Aachen, RWTH Aachen University, Aachen, Germany
| | - Kinan Kneizeh
- Department of Cardiology, Angiology and Internal Intensive Medicine, University Hospital Aachen, RWTH Aachen University, Aachen, Germany
| | - Christian Cornelissen
- Department of Pneumology, University Hospital Aachen, RWTH Aachen University, Aachen, Germany
| | - Vincent Brandenburg
- Department of Cardiology and Nephrology, Rhein-Maas Klinikum, Wuerselen, Germany
| | - Elisa Liehn
- Department of Cardiology, Angiology and Internal Intensive Medicine, University Hospital Aachen, RWTH Aachen University, Aachen, Germany
| | - Alexander Schuh
- Department of Internal Medicine I, St. Katharinen Hospital Frechen, Kapellenstrasse 1-5, 50226, Frechen, Germany.
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Inflammation: a putative link between phosphate metabolism and cardiovascular disease. Clin Sci (Lond) 2021; 135:201-227. [PMID: 33416083 PMCID: PMC7796315 DOI: 10.1042/cs20190895] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 12/11/2020] [Accepted: 12/15/2020] [Indexed: 02/06/2023]
Abstract
Dietary habits in the western world lead to increasing phosphate intake. Under physiological conditions, extraosseous precipitation of phosphate with calcium is prevented by a mineral buffering system composed of calcification inhibitors and tight control of serum phosphate levels. The coordinated hormonal regulation of serum phosphate involves fibroblast growth factor 23 (FGF23), αKlotho, parathyroid hormone (PTH) and calcitriol. A severe derangement of phosphate homeostasis is observed in patients with chronic kidney disease (CKD), a patient collective with extremely high risk of cardiovascular morbidity and mortality. Higher phosphate levels in serum have been associated with increased risk for cardiovascular disease (CVD) in CKD patients, but also in the general population. The causal connections between phosphate and CVD are currently incompletely understood. An assumed link between phosphate and cardiovascular risk is the development of medial vascular calcification, a process actively promoted and regulated by a complex mechanistic interplay involving activation of pro-inflammatory signalling. Emerging evidence indicates a link between disturbances in phosphate homeostasis and inflammation. The present review focuses on critical interactions of phosphate homeostasis, inflammation, vascular calcification and CVD. Especially, pro-inflammatory responses mediating hyperphosphatemia-related development of vascular calcification as well as FGF23 as a critical factor in the interplay between inflammation and cardiovascular alterations, beyond its phosphaturic effects, are addressed.
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20
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Memmos E, Papagianni A. New Insights into the Role of FGF-23 and Klotho in Cardiovascular Disease in Chronic Kidney Disease Patients. Curr Vasc Pharmacol 2021; 19:55-62. [PMID: 32310050 DOI: 10.2174/1570161118666200420102100] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 03/10/2020] [Accepted: 03/11/2020] [Indexed: 12/29/2022]
Abstract
Alterations of fibroblast growth factor 23 (FGF-23) and Klotho levels are considered to be the earliest biochemical abnormality of chronic kidney disease - mineral and bone disease (CKDMBD) syndrome. Moreover, emerging data suggests that the dysregulated FGF-23 and Klotho axis has many effects on the cardiovascular (CV) system and contributes significantly to the increased CV morbidity and mortality rates of CKD patients. This review examines recent evidence on the role of FGF-23 and Klotho in the development and progression of CV complications of uremia namely cardiac hypertrophy, uremic cardiomyopathy, and atherosclerotic and arteriosclerotic vascular lesions. Moreover, the available evidence on their associations with adverse clinical outcomes are summarized. Undoubtedly, more studies are needed to further elucidate the effects of FGF-23 and Klotho on the heart and vessels and to gain insights into their prognostic value as CV risk factors. Finally, large prospective studies are required to test the hypothesis that modification of their levels would have a favourable impact on the unacceptably high mortality rates of these patient populations.
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Affiliation(s)
- Evangelos Memmos
- Department of Nephrology, Aristotle University of Thessaloniki, General Hospital "Hippokratio", Thessaloniki, Greece
| | - Aikaterini Papagianni
- Department of Nephrology, Aristotle University of Thessaloniki, General Hospital "Hippokratio", Thessaloniki, Greece
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21
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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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22
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Bi X, Zhang Q, Zhuang F, Lu W, Wang Y, Ding F. An Observational Cohort Study of the 2-Month Use of Regional Citrate Anticoagulation in Maintenance Hemodialysis Patients with Cerebral Hemorrhage. Med Sci Monit 2021; 27:e930513. [PMID: 33859156 PMCID: PMC8056873 DOI: 10.12659/msm.930513] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background Regional citrate anticoagulation (RCA) is a recommended anticoagulation alternative for patients at high risk of bleeding while undergoing intermittent hemodialysis. Previous reports implied the risk of citrate application on bone metabolism. It is unclear whether long-term use of RCA is safe for maintenance hemodialysis patients in terms of bone metabolism. Material/Methods Seven patients with cerebral hemorrhage were included in the study. Blood samples were collected at baseline and 4 and 8 weeks after treatment. Spent dialysate samples were collected during each mid-week dialysis session, using the partial dialysate collection method. All patients were treated with RCA for 4 to 8 weeks, according to their clinical condition. We assessed bone metabolism-associated parameters, bone turnover markers, and magnesium loss at each dialysis session. Results Serum magnesium levels were 1.24±0.13 mmol/L at baseline and significantly decreased to 1.16±0.14 mmol/L after 4 weeks of RCA treatment (P=0.025). Most patients had negative magnesium balance during citrate hemodialysis. Serum total calcium levels did not change significantly after treatment. One bone marker, N-terminal propeptide of type I procollagen (PINP), significantly decreased from 146.07±130.12 mmol/L to 92.42±79.01 mmol/L after citrate treatment (P=0.018). No significant changes were detected in other bone turnover markers. Conclusions Relatively long-term RCA treatment may decrease serum magnesium levels due to negative magnesium balance. Bone formation marker PINP seemed to decrease after treatment, while other bone turnover markers did not change significantly. Further investigation is needed to verify the effect of RCA on bone remodeling.
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Affiliation(s)
- Xiao Bi
- Division of Nephrology and Critical Care Nephrology Unit, Shanghai Ninth People's Hospital, Shanghai JiaoTong University, School of Medicine, Shanghai, China (mainland)
| | - Qi Zhang
- Division of Nephrology and Critical Care Nephrology Unit, Shanghai Ninth People's Hospital, Shanghai JiaoTong University, School of Medicine, Shanghai, China (mainland)
| | - Feng Zhuang
- Division of Nephrology and Critical Care Nephrology Unit, Shanghai Ninth People's Hospital, Shanghai JiaoTong University, School of Medicine, Shanghai, China (mainland)
| | - Wei Lu
- Division of Nephrology and Critical Care Nephrology Unit, Shanghai Ninth People's Hospital, Shanghai JiaoTong University, School of Medicine, Shanghai, China (mainland)
| | - Yingdeng Wang
- Division of Nephrology and Critical Care Nephrology Unit, Shanghai Ninth People's Hospital, Shanghai JiaoTong University, School of Medicine, Shanghai, China (mainland)
| | - Feng Ding
- Division of Nephrology and Critical Care Nephrology Unit, Shanghai Ninth People's Hospital, Shanghai JiaoTong University, School of Medicine, Shanghai, China (mainland)
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Hanudel MR, Wong S, Jung G, Qiao B, Gabayan V, Zuk A, Ganz T. Amelioration of chronic kidney disease-associated anemia by vadadustat in mice is not dependent on erythroferrone. Kidney Int 2021; 100:79-89. [PMID: 33811979 DOI: 10.1016/j.kint.2021.03.019] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 02/02/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023]
Abstract
Vadadustat is an investigational hypoxia-inducible factor prolyl hydroxylase inhibitor that increases endogenous erythropoietin production and has been shown to decrease hepcidin levels, ameliorate iron restriction, and increase hemoglobin concentrations in anemic patients with chronic kidney disease (CKD). In studies of physiological responses to other erythropoietic stimuli, erythropoietin induced erythroblast secretion of erythroferrone (ERFE), which acts on the liver to suppress hepcidin production and mobilize iron for erythropoiesis. We therefore investigated whether vadadustat effects on erythropoiesis and iron metabolism are dependent on ERFE. Wild type and ERFE knockout mice with and without CKD were treated with vadadustat or vehicle. In both wild type and ERFE knockout CKD models, vadadustat was similarly effective, as evidenced by normalized hemoglobin concentrations, increased expression of duodenal iron transporters, lower serum hepcidin levels, and decreased tissue iron concentrations. This is consistent with ERFE-independent increased iron mobilization. Vadadustat treatment also lowered serum urea nitrogen and creatinine concentrations and decreased expression of kidney fibrosis markers. Lastly, vadadustat affected fibroblast growth factor 23 (FGF23) profiles: in non-CKD mice, vadadustat increased plasma total FGF23 out of proportion to intact FGF23, consistent with the known effects of hypoxia-inducible factor-1α and erythropoietin on FGF23 production and metabolism. However, in the mice with CKD, vadadustat markedly decreased both total and intact FGF23, effects likely contributed to by the reduced loss of kidney function. Thus, in this CKD model, vadadustat ameliorated anemia independently of ERFE, improved kidney parameters, and decreased FGF23. How vadadustat affects CKD progression in humans warrants future studies.
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Affiliation(s)
- Mark R Hanudel
- Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA.
| | - Shirley Wong
- Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - Grace Jung
- Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - Bo Qiao
- Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - Victoria Gabayan
- Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - Anna Zuk
- Research and Development, Akebia Therapeutics, Inc., Cambridge, Massachusetts, USA
| | - Tomas Ganz
- Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
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Mirna M, Lauten A, Jirak P, Rezar R, Wernly B, Paar V, Felder TK, Hoppe UC, Motloch LJ, Jung C, Alushi B, Lichtenauer M, Salmhofer H. Serum levels of C-terminal FGF23 (cFGF23) are associated with 1-year-mortality in patients undergoing transcatheter aortic valve replacement (TAVR). Eur J Intern Med 2021; 85:98-107. [PMID: 33191056 DOI: 10.1016/j.ejim.2020.09.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 08/23/2020] [Accepted: 09/23/2020] [Indexed: 11/22/2022]
Abstract
INTRODUCTION Serum levels of FGF23 have been associated with adverse outcomes in cardiovascular diseases in patients with and without impaired renal function. Hence, this study aimed to explore the prognostic relevance of intact FGF23 (iFGF23) and its derivate C-terminal FGF23 (cFGF23) in patients undergoing transcatheter aortic valve replacement (TAVR) with regard to renal function. METHODS A total of 274 patients undergoing transfemoral TAVR were enrolled in this study. Blood samples were obtained preinterventionally and analyzed for iFGF23 and cFGF23 by means of enzyme linked immunosorbent assay (ELISA). Follow-up was obtained for 12 months. RESULTS Serum levels of cFGF23 and iFGF23 both correlated positively with serum creatinine and inversely with estimated glomerular filtration rate (eGFR). Cox regression analysis revealed a significant association of cFGF23 with 1-year-mortality in patients with eGFR ≥45ml/min/1.73m², but not in patients with an eGFR <45ml/min/1.73m². A cut-off was calculated for cFGF23 (6.82 pmol/l) and patients with eGFR ≥45ml/min/1.73m² were retrospectively divided into two groups (above/below cut-off). Patients above the cut-off had a significantly worse 1-year-mortality than patients below the cut-off (33.3% vs. 19.6%; OR 2.05 (95%CI 1.03-4.07), p= 0.038). The association of cFGF23 with 1-year-mortality in patients with eGFR ≥45ml/min/1.73m² remained statistically significant even after correction for possible confounders in a multivariate Cox regression analysis. CONCLUSION cFGF23 could be an individual risk factor for mortality in patients undergoing TAVR with an eGFR ≥45ml/min/1.73m².
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Affiliation(s)
- Moritz Mirna
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University of Salzburg, Müllner Hauptstraße 48, 5020 Salzburg, Austria.
| | - Alexander Lauten
- Department of General and Interventional Cardiology and Rhythmology, Helios Clinic, Erfurt, Germany
| | - Peter Jirak
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University of Salzburg, Müllner Hauptstraße 48, 5020 Salzburg, Austria
| | - Richard Rezar
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University of Salzburg, Müllner Hauptstraße 48, 5020 Salzburg, Austria
| | - Bernhard Wernly
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University of Salzburg, Müllner Hauptstraße 48, 5020 Salzburg, Austria
| | - Vera Paar
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University of Salzburg, Müllner Hauptstraße 48, 5020 Salzburg, Austria
| | - Thomas K Felder
- Department of Laboratory Medicine, Paracelsus Medical University of Salzburg, Salzburg, Austria
| | - Uta C Hoppe
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University of Salzburg, Müllner Hauptstraße 48, 5020 Salzburg, Austria
| | - Lukas J Motloch
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University of Salzburg, Müllner Hauptstraße 48, 5020 Salzburg, Austria
| | - Christian Jung
- Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Duesseldorf, Germany
| | - Brunilda Alushi
- Department of General and Interventional Cardiology and Rhythmology, Helios Clinic, Erfurt, Germany
| | - Michael Lichtenauer
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University of Salzburg, Müllner Hauptstraße 48, 5020 Salzburg, Austria
| | - Hermann Salmhofer
- Department of Internal Medicine I, Division of Gastroenterology and Nephrology, Paracelsus Medical University of Salzburg, Austria
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Jiang L, Yin Q, Yang M, Li M, Pan M, Han Y, Zhao Z, Wang Z, Zhu L, Wei Q, Tu Y, Gao M, Liu H, Zhang X, Liu BC, Wang B. Fibroblast Growth Factor 21 Predicts and Promotes Vascular Calcification in Haemodialysis Patients. KIDNEY DISEASES 2021; 7:227-240. [PMID: 34179118 DOI: 10.1159/000512750] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 10/31/2020] [Indexed: 01/02/2023]
Abstract
Background Cardiovascular disease (CVD) is the leading cause of death in haemodialysis (HD) patients. Vascular calcification (VC) is dramatically accelerated and is strongly associated with CVD events and mortality in HD patients. VC coexists with osteoporosis in many studies. Fibroblast growth factor 21 (FGF21) which is known as an adipocytokine is a new hypoglycemic strategy and is inversely related to bone mineral density. Methods To evaluate the contribution of FGF21 to VC in HD patients, we detected circulating FGF21 levels and measured the whole thoracic aorta calcification scores (TACS) and calcification scores of the 3 segments of thoracic aorta, including ascending thoracic aorta (ATACS), aortic arch (AoACS), and descending thoracic aorta (DTACS) of our HD patients in this cross-sectional study. In addition, we pre-incubated human aortic endothelial cells (HAECs) with FGF21 in the presence or absence of parathyroid hormone (PTH) in vitro. Results The median serum FGF21 level in HD patients was 11-fold higher than that in healthy controls. Ln(FGF21) was positively correlated with Ln(TACS+1), Ln(ATACS+1), Ln(AoACS+1), and Ln(DTACS+1), respectively, in HD patients. Serum FGF21 was independently associated with TACS and ATACS, AoACS, and DTACS. FGF21 which was combined with age, calcium, and intact PTH demonstrated a high area under the curve of 0.84 with optimal sensitivity (84%) and specificity (71%) for the prediction of VC in HD patients. Our vitro results showed that FGF21 enhanced the calcification effect of PTH on HAECs by increasing calcium deposition and endothelial-to-mesenchymal transition. Conclusions Circulating FGF21 was notably higher and was a potential predictor and promoter of VC in HD patients.
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Affiliation(s)
- Liqiong Jiang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China.,Department of Nephrology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Qing Yin
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Min Yang
- Department of Nephrology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Min Li
- Department of Nephrology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Mingming Pan
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Yuchen Han
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Zhen Zhao
- Department of Radiology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Zhi Wang
- Department of Radiology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Lili Zhu
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Qing Wei
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Yan Tu
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Min Gao
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Hong Liu
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Xiaoliang Zhang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Bi-Cheng Liu
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Bin Wang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
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Asicioglu E, Velioglu A, Arikan H, Koc M, Tuglular S, Ozener C. Baseline carotid intima-media thickness is associated with cardiovascular morbidity and mortality in peritoneal dialysis patients. Ther Apher Dial 2021; 25:962-969. [PMID: 33511768 DOI: 10.1111/1744-9987.13629] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 01/13/2021] [Accepted: 01/26/2021] [Indexed: 12/19/2022]
Abstract
Carotid intima-media thickness (CIMT) is an early marker of atherosclerosis and is increased in peritoneal dialysis (PD) patients. Association of CIMT with cardiovascular disease (CVD) or mortality is less clear. Fibroblast growth factor-23 (FGF-23) is a hormone associated with vascular calcification, atherosclerosis, and mortality in the hemodialysis population. We investigated whether baseline CIMT and FGF-23 are associated with CVD and mortality in PD patients. Fifty-five PD patients were included. CVD was defined as ischemic heart disease, stroke, or peripheral artery disease. Intact FGF-23 was measured in plasma. CIMT was measured by ultrasonography. Twenty-one patients developed CVD and 12 died over 47.1 ± 33.8 months. Patients with CVD were older (55.9 ± 10.5 vs. 42.5 ± 12.9 years, P < .01), had lower albumin (3.8 ± 0.5 vs. 4.2 ± 0.3 g/dL, P < .01) and higher CIMT (0.87 ± 0.22 vs. 0.61 ± 0.11 mm, P < .01). Patients with mortality were also older (53.5 ± 11.5 vs. 45.8 ± 13.8 years, P = .05), had lower albumin (3.7 ± 0.6 vs. 4.1 ± 0.3 g/dL, P < .01), higher CRP (15.0 ± 8.5 vs. 7.6 ± 8.4 mg/L, P < .01) and CIMT (0.9 ± 0.3 vs. 0.6 ± 0.1 mm, P < .01). Albumin and CIMT were associated with CVD and CIMT > 0.75 mm was associated with cardiovascular mortality. FGF-23 did not show any correlations. CIMT at baseline is associated with CVD and mortality in PD patients.
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Affiliation(s)
- Ebru Asicioglu
- Department of Nephrology, Marmara University Pendik Teaching Hospital, Istanbul, Turkey
| | - Arzu Velioglu
- Department of Nephrology, Marmara University Pendik Teaching Hospital, Istanbul, Turkey
| | - Hakki Arikan
- Department of Nephrology, Marmara University Pendik Teaching Hospital, Istanbul, Turkey
| | - Mehmet Koc
- Department of Nephrology, Marmara University Pendik Teaching Hospital, Istanbul, Turkey
| | - Serhan Tuglular
- Department of Nephrology, Marmara University Pendik Teaching Hospital, Istanbul, Turkey
| | - Cetin Ozener
- Department of Nephrology, Marmara University Pendik Teaching Hospital, Istanbul, Turkey
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Balmukhanova A, Kabulbayev K, Alpay H, Kanatbayeva A, Balmukhanova A. FGF-23 and Phosphate in Children with Chronic Kidney Disease: A Cross-Sectional Study in Kazakhstan. ACTA ACUST UNITED AC 2020; 57:medicina57010015. [PMID: 33379157 PMCID: PMC7823813 DOI: 10.3390/medicina57010015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 12/21/2020] [Accepted: 12/22/2020] [Indexed: 11/16/2022]
Abstract
Background and objectives: Chronic kidney disease (CKD) in children is a complex medical and social issue around the world. One of the serious complications is mineral-bone disorder (CKD-MBD) which might determine the prognosis of patients and their quality of life. Fibroblast growth factor 23 (FGF-23) is a phosphaturic hormone which is involved in the pathogenesis of CKD-MBD. The purpose of the study was to determine what comes first in children with CKD: FGF-23 or phosphate. Materials and Methods: This cross-sectional study included 73 children aged 2-18 years with CKD stages 1-5. We measured FGF-23 and other bone markers in blood samples and studied their associations. Results: Early elevations of FGF-23 were identified in children with CKD stage 2 compared with stage 1 (1.6 (1.5-1.8) pmol/L versus 0.65 (0.22-1.08), p = 0.029). There were significant differences between the advanced stages of the disease. FGF-23 correlated with PTH (r = 0.807, p = 0.000) and phosphate (r = 0.473, p = 0.000). Our study revealed that the elevated level of FGF-23 went ahead hyperphosphatemia and elevated PTH. Thus, more than 50% of children with CKD stage 2 had the elevating level of serum FGF-23, and that index became increasing with the disease progression and it achieved 100% at the dialysis stage. The serum phosphate increased more slowly and only 70.6% of children with CKD stage 5 had the increased values. The PTH increase was more dynamic. Conclusions: FGF-23 is an essential biomarker, elevates long before other markers of bone metabolism (phosphate), and might represent a clinical course of disease.
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Affiliation(s)
- Altynay Balmukhanova
- Department of Nephrology, Asfendiyarov Kazakh National Medical University, Almaty 050000, Kazakhstan; (K.K.); (A.K.)
- Correspondence: ; Tel.: +7-701-754-6850
| | - Kairat Kabulbayev
- Department of Nephrology, Asfendiyarov Kazakh National Medical University, Almaty 050000, Kazakhstan; (K.K.); (A.K.)
| | - Harika Alpay
- Division of Pediatric Nephrology, Marmara University, 34899 Pendik, Turkey;
| | - Assiya Kanatbayeva
- Department of Nephrology, Asfendiyarov Kazakh National Medical University, Almaty 050000, Kazakhstan; (K.K.); (A.K.)
| | - Aigul Balmukhanova
- Department of Science and Innovations, Asfendiyarov Kazakh National Medical University, Almaty 050000, Kazakhstan;
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Komaba H, Fuller DS, Taniguchi M, Yamamoto S, Nomura T, Zhao J, Bieber BA, Robinson BM, Pisoni RL, Fukagawa M. Fibroblast Growth Factor 23 and Mortality Among Prevalent Hemodialysis Patients in the Japan Dialysis Outcomes and Practice Patterns Study. Kidney Int Rep 2020; 5:1956-1964. [PMID: 33163716 PMCID: PMC7609896 DOI: 10.1016/j.ekir.2020.08.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 08/04/2020] [Accepted: 08/11/2020] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION Elevated fibroblast growth factor 23 (FGF23) levels have been strongly associated with mortality in the predialysis and incident hemodialysis populations, but few studies have examined this relationship in a large cohort of prevalent hemodialysis patients and in particular among persons with high dialysis vintage. To address this, we analyzed data from the Japan Dialysis Outcomes and Practice Patterns Study (J-DOPPS). METHODS We included 1122 prevalent hemodialysis patients from the J-DOPPS phase 5 (2012-2015) who had FGF23 measurements. We evaluated the association of FGF23 levels with all-cause mortality and cardiovascular composite outcome using Cox regression adjusted for potential confounders. RESULTS At study enrollment, median dialysis vintage was 5.8 years (interquartile range, 2.7-12.4 years) and median FGF23 level was 2113 pg/ml (interquartile range, 583-6880 pg/ml). During 3-year follow-up, 154 of the 1122 participants died. In adjusted analyses, higher FGF23 was associated with a greater hazard of death (hazard ratio per doubling of FGF23, 1.12; 95% confidence interval, 1.03-1.21); however, the association became weaker as the dialysis vintage increased and finally disappeared in the highest tertile (>9.4 years). Similar patterns of effect modification by dialysis vintage were observed for cardiovascular composite outcome and in time-dependent models. CONCLUSION Elevated FGF23 was associated with mortality and cardiovascular events in prevalent hemodialysis patients, but the association was attenuated at longer dialysis vintages. This novel finding suggests that long-term hemodialysis patients may be less susceptible to the detrimental effects of FGF23 or correlated biological processes, and additional studies are needed to gain understanding of these possibilities.
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Affiliation(s)
- Hirotaka Komaba
- Division of Nephrology, Endocrinology, and Metabolism, Tokai University School of Medicine, Isehara, Japan
- The Institute of Medical Sciences, Tokai University, Isehara, Japan
| | | | | | - Suguru Yamamoto
- Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Takanobu Nomura
- Medical Affairs Department, Kyowa Kirin Co., Ltd., Tokyo, Japan
| | - Junhui Zhao
- Arbor Research Collaborative for Health, Ann Arbor, Michigan, USA
| | - Brian A. Bieber
- Arbor Research Collaborative for Health, Ann Arbor, Michigan, USA
| | | | - Ronald L. Pisoni
- Arbor Research Collaborative for Health, Ann Arbor, Michigan, USA
| | - Masafumi Fukagawa
- Division of Nephrology, Endocrinology, and Metabolism, Tokai University School of Medicine, Isehara, Japan
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Parker VJ, Rudinsky AJ, Benedict JA, Beizaei A, Chew DJ. Effects of calcifediol supplementation on markers of chronic kidney disease-mineral and bone disorder in dogs with chronic kidney disease. J Vet Intern Med 2020; 34:2497-2506. [PMID: 33128421 PMCID: PMC7694821 DOI: 10.1111/jvim.15949] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 10/11/2020] [Accepted: 10/19/2020] [Indexed: 12/18/2022] Open
Abstract
Background Chronic kidney disease‐mineral and bone disorder (CKD‐MBD) in dogs is associated with hypovitaminosis D, increased parathyroid hormone (PTH), and increased fibroblast growth factor‐23 (FGF‐23) concentrations. Best practice for vitamin D metabolite supplementation in CKD‐MBD remains unknown. Objective To provide an extended‐release calcifediol supplement to dogs with CKD and to measure its effects on variables indicative of CKD‐MBD. Animals Ten dogs with International Renal Interest Society stages 2 and 3 CKD. Methods In a prospective study, dogs received a calcifediol supplement for 84 days. Serum 25‐hydroxyvitamin D (25[OH]D), 1,25‐dihydroxyvitamin D (1,25[OH]2D), 24,25‐dihydroxyvitamin D (24,25[OH]2D), creatinine, calcium, phosphorus, PTH, plasma FGF‐23 concentrations, and urine profiles were measured monthly during supplementation. Urine calcium to creatinine (UCa/Cr) ratios and fractional excretion of calcium, phosphorus, and sodium were determined. Results All serum vitamin D metabolite concentrations increased significantly by day 84 (P < .001): [25(OH)D (median 249.9 ng/mL; range, 149.7‐469.9 ng/mL) compared to baseline (median 50.2 ng/mL; range, 31.3‐66.0 ng/mL); 1,25(OH)2D (median 66.1 pg/mL; range, 56.9‐88.1 pg/mL) compared to baseline (median 37.3 pg/mL; range, 29.3‐56.7 pg/mL); 24,25(OH)2D (median 81.4 ng/mL; range, 22.1‐151.7 ng/mL) compared to baseline (median 15.4 ng/mL; range, 6.9‐40.6 ng/mL)]. There were no significant differences in calcium, phosphorus, PTH concentrations, UCa/Cr or fractional excretion of calcium. No dog developed ionized hypercalcemia. Plasma FGF‐23 concentrations increased by day 84 (median 1219 pg/mL; range, 229‐8824 pg/mL) compared to baseline (median 798 pg/mL; range, 103‐4.145 pg/mL) (P < .01). Conclusions and Clinical Importance Calcifediol supplementation for 84 days was well‐tolerated in dogs with IRIS stages 2 and 3 CKD. It remains to be determined how long‐term supplementation would affect CKD progression and QOL.
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Affiliation(s)
- Valerie J Parker
- Veterinary Clinical Sciences, The Ohio State University Veterinary Medical Center, Columbus, Ohio, USA
| | - Adam J Rudinsky
- Veterinary Clinical Sciences, The Ohio State University Veterinary Medical Center, Columbus, Ohio, USA
| | - Jason A Benedict
- Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, Ohio, USA
| | - Azadeh Beizaei
- EirGen Pharma LTD, R&D Center, IDA Business and Technology Park, Waterford, Ireland
| | - Dennis J Chew
- Veterinary Clinical Sciences, The Ohio State University Veterinary Medical Center, Columbus, Ohio, USA
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30
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Tang R, Lu Y, Yin R, Zhu P, Zhu L, Zheng C. The Effects of Storage Time and Repeated Freeze-Thaw Cycles on Intact Fibroblast Growth Factor 23 Levels. Biopreserv Biobank 2020; 19:48-52. [PMID: 33085535 DOI: 10.1089/bio.2020.0073] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Background: Fibroblast growth factor 23 (FGF23) has become increasingly important in chronic kidney diseases (CKDs), cardiovascular calcification, and metabolic bone diseases. Fresh or stored blood samples are widely used for the FGF23 assay. Clarifying the factors influencing the FGF23 assay can help to quantify FGF23 more accurately. This study explored the effects of low-temperature storage time and repeated freeze-thaw cycles on the measurement of serum intact FGF23 (iFGF23). Materials and Methods: We selected 60 serum samples from patients with CKD stages 3-5 and hemodialysis patients. An enzyme-linked immunosorbent assay was used to measure the changes in serum iFGF23 levels after 6 years of storage at -80°C. In total, 18 fresh serum samples were frozen and thawed for 0, 1, 3, and 5 cycles to explore the effects of repeated freeze-thaw cycles on serum iFGF23 levels. Results: Median serum iFGF23 concentrations were 252.17 (interquartile range [IQR] 113.82-592.38) pg/mL and 203.85 (IQR 64.76-545.39) pg/mL before and after 6 years. There were no significant differences between them. However, we found a downward trend of 48% in the samples close to the normal level of iFGF23 (<150.34 pg/mL) after 6 years of storage (p = 0.160). In addition, the iFGF23 levels of samples frozen and thawed for 0, 1, 3, and 5 cycles were 278.41 ± 39.51 (mean ± standard deviation) pg/mL, 262.84 ± 38.42 pg/mL, 252.97 ± 34.65 pg/mL and 250.49 ± 37.12 pg/mL, respectively. A slight downward trend in iFGF23 levels was observed with increasing freeze-thaw times; however, no significant differences were found among different freeze-thaw cycles. Conclusion: Serum iFGF23 levels remained stable after storage at -80°C for 6 years. In addition, five freeze-thaw cycles had no significant effects on serum iFGF23 levels.
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Affiliation(s)
- Rong Tang
- National Clinical Research Center of Kidney Diseases, Nanjing University School of Medicine, Jinling Hospital, Nanjing, China
| | - Yinghui Lu
- National Clinical Research Center of Kidney Diseases, Nanjing University School of Medicine, Jinling Hospital, Nanjing, China
| | - Ru Yin
- National Clinical Research Center of Kidney Diseases, Nanjing University School of Medicine, Jinling Hospital, Nanjing, China
| | - Ping Zhu
- National Clinical Research Center of Kidney Diseases, Nanjing University School of Medicine, Jinling Hospital, Nanjing, China
| | - Ling Zhu
- National Clinical Research Center of Kidney Diseases, Nanjing University School of Medicine, Jinling Hospital, Nanjing, China
| | - Chunxia Zheng
- National Clinical Research Center of Kidney Diseases, Nanjing University School of Medicine, Jinling Hospital, Nanjing, China
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Manou E, Thodis E, Arsos G, Pasadakis P, Panagoutsos S, Papadopoulou D, Papagianni A. Fibroblast Growth Factor 23 and α-Klotho Protein Are Associated with Adverse Clinical Outcomes in Non-Dialysis CKD Patients. Kidney Blood Press Res 2020; 45:900-915. [PMID: 33040068 DOI: 10.1159/000510351] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 07/22/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Fibroblast growth factor 23 (FGF-23) and α-Klotho protein appear to have an important role in the pathogenesis of CKD-mineral and bone disorders. The aim of this study was to investigate the association of FGF-23 and α-Klotho levels with adverse clinical outcomes in patients with non-dialysis CKD. MATERIALS AND METHODS We conducted a prospective cohort study, enrolling participants with non-dialysis CKD from a single center in Greece. At enrollment, glomerular filtration rate (GFR) was measured (mGFR) and plasma levels of carboxyl terminal FGF-23 (cFGF-23) and soluble α-Klotho (sKlotho) were determined by enzyme-linked immunoassay. Participants were followed for up to 5 years or until the occurrence of the primary endpoint of initiation of renal replacement therapy or death. Multivariate regression tree analysis was used to identify informative baseline parameters in order to categorize participants. Also, using median values of cFGF-23 and sKlotho, participants were categorized into 4 groups, in whom survival was compared using Kaplan-Meier and Cox regression analysis. RESULTS 128 participants were enrolled with a median mGFR of 41.5 mL/min/1.73 m2 (IQR = 28.2). Baseline mGFR correlated with cFGF-23 and sKlotho (r = -0.54 and r = 0.49, respectively; p < 0.0001 for both). cFGF-23 and sKlotho levels correlated negatively (r = -0.24, p = 0.006). Multivariate regression tree analysis resulted in 3 groups defined by cutoff values of mGFR (60.9 mL/min/1.73 m2) and phosphate (3.7 mg/dL). These groups correlated with CKD stage, cFGF-23, and sKlotho (p < 0.0001 for all). During a median follow-up of 36 months (IQR = 22), 40 (31.2%) participants reached the primary endpoint (31 initiated renal replacement therapy, 9 died). Survival to primary endpoint differed among the 4 groups formed using median values of both biomarkers, with the low FGF-23/high Klotho and high FGF-23/low Klotho having the longest and shortest survival, respectively. High FGF-23/low Klotho group, compared to the opposite one, had a significantly elevated risk of the primary outcome (HR, 6.8; 95% CI, 2.3-19.6; p = 0.0004). CONCLUSIONS In patients with CKD stages 1-5, the combination of higher cFGF-23 and lower sKlotho levels along with mGFR and serum phosphate was associated with adverse clinical outcomes. The utility of combinations of traditional and novel biomarkers to predict outcomes warrants further study.
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Affiliation(s)
- Eleni Manou
- Department of Nephrology, Papageorgiou Hospital, Thessaloniki, Greece,
| | - Elias Thodis
- Department of Nephrology, Democritus University of Thrace, Alexandroupolis, Greece
| | - Georgios Arsos
- 3rd Department of Nuclear Medicine, Aristotle University of Thessaloniki, Papageorgiou Hospital, Thessaloniki, Greece
| | - Ploumis Pasadakis
- Department of Nephrology, Democritus University of Thrace, Alexandroupolis, Greece
| | | | | | - Aikaterini Papagianni
- Department of Nephrology, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
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Block GA, Chertow GM, Cooper K, Xing S, Fouqueray B, Halperin M, Danese MD. Fibroblast growth factor 23 as a risk factor for cardiovascular events and mortality in patients in the EVOLVE trial. Hemodial Int 2020; 25:78-85. [PMID: 33016505 DOI: 10.1111/hdi.12887] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 09/17/2020] [Accepted: 09/18/2020] [Indexed: 01/10/2023]
Abstract
INTRODUCTION High mortality rates in patients with chronic kidney disease-mineral and bone disorder (CKD-MBD) receiving maintenance hemodialysis are largely due to cardiovascular (CV) events. METHODS We evaluated associations between MBD parameters, fibroblast growth factor 23 (FGF23) concentrations, and clinically adjudicated CV events from the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial. Patients enrolled in EVOLVE, who had not experienced any study endpoints between randomization and week 20 with evaluable baseline and week 20 values for key laboratory parameters (parathyroid hormone, calcium, phosphate, and FGF23), were assessed. We used adjusted Cox proportional hazards regression models to estimate relative risk of outcomes (primary composite, all-cause mortality, and CV events) based on FGF23 and MBD parameters. Laboratory values were modeled with linear terms and using natural cubic splines with two degrees of freedom. FINDINGS For the primary endpoint, patients assessed (N = 2309) were followed up over a mean duration of 3.1 years, during which 1037 CV events (497 deaths, 540 nonfatal events) occurred. Adjusted models showed an association between FGF23 and the risk of CV events. Hazard ratio per log unit of FGF23 at week 20 was 1.09 [95% CI: 1.03-1.16], and the hazard ratio per log unit change in FGF23 from week 0 to week 20 was 1.09 [95% CI: 1.00-1.17]. DISCUSSION Our data highlight FGF23 as an independent CV risk factor and potential biomarker and therapeutic target for patients with CKD-MBD receiving maintenance hemodialysis.
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Affiliation(s)
| | - Glenn M Chertow
- Stanford University School of Medicine, Palo Alto, California, USA
| | | | - Shan Xing
- Amgen Inc., Thousand Oaks, California, USA
| | | | - Marc Halperin
- Outcomes Insights, Inc., Agoura Hills, California, USA
| | - Mark D Danese
- Outcomes Insights, Inc., Agoura Hills, California, USA
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Vervloet MG. FGF23 measurement in chronic kidney disease: What is it really reflecting? Clin Chim Acta 2020; 505:160-166. [PMID: 32156608 DOI: 10.1016/j.cca.2020.03.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 03/05/2020] [Accepted: 03/06/2020] [Indexed: 12/20/2022]
Abstract
Fibroblast growth factor can be measured in clinical practice using ELISA, with acceptable validity. Different from many metabolites and minerals, its value can differ by a thousand-fold between individuals, largely because of differences in kidney function and dietary habits. This wide range complicates the proper interpretation of the concentration of FGF23, both in terms of the appropriateness of a given value for a given estimated GFR, and in terms of estimating the magnitude of risk for clinical events, with which FGF23 is clearly associated. In this narrative review, the impact of kidney function, exposure to phosphate from diet, and novel emerging factors that influence FGF23 concentrations are discussed. These and yet to define determinants of FGF23 question the causality of the association of FGF23 with hard (cardiovascular) endpoints, as observed in several epidemiological studies.
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Affiliation(s)
- Marc G Vervloet
- Amsterdam University Medical Center, Department of Nephrology, and Amsterdam Cardiovascular Sciences (ACS), Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
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Bouma-de Krijger A, Vervloet MG. Fibroblast growth factor 23: are we ready to use it in clinical practice? J Nephrol 2020; 33:509-527. [PMID: 32130720 PMCID: PMC7220896 DOI: 10.1007/s40620-020-00715-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 02/15/2020] [Indexed: 12/15/2022]
Abstract
Patients with chronic kidney disease (CKD) have a greatly enhanced risk of cardiovascular morbidity and mortality. Over the past decade it has come clear that a disturbed calcium-phosphate metabolism, with Fibroblast Growth Factor-23 as a key hormone, is partly accountable for this enhanced risk. Numerous studies have been performed unravelling FGF23s actions and its association with clinical conditions. As FGF23 is strongly associated with adverse outcome it may be a promising biomarker for risk prediction or, even more important, targeting FGF23 may be a strategy to improve patient outcome. This review elaborates on the clinical usefulness of FGF23 measurement. Firstly it discusses the reliability of the FGF23 measurement. Secondly, it evaluates whether FGF23 measurement may lead to improved patient risk classification. Finally, and possibly most importantly, this review evaluates if lowering of FGF23 should be a target for therapy. For this, the review discusses the current evidence indicating that FGF23 may be in the causal pathway to cardiovascular pathology, provides an overview of strategies to lower FGF23 levels and discusses the current evidence concerning the benefit of lowering FGF23.
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Affiliation(s)
- Annet Bouma-de Krijger
- Department of Nephrology, Amsterdam Cardiovascular Science, Amsterdam University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - Marc G. Vervloet
- Department of Nephrology, Amsterdam Cardiovascular Science, Amsterdam University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
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Rodríguez-Ortiz ME, Alcalá-Díaz JF, Canalejo A, Torres-Peña JD, Gómez-Delgado F, Muñoz-Castañeda JR, Delgado-Lista J, Rodríguez M, López-Miranda J, Almadén Y. Fibroblast growth factor 23 predicts carotid atherosclerosis in individuals without kidney disease. The CORDIOPREV study. Eur J Intern Med 2020; 74:79-85. [PMID: 31899053 DOI: 10.1016/j.ejim.2019.12.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 12/15/2019] [Accepted: 12/17/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Fibroblast growth factor 23 (FGF23) is a major determinant of mineral metabolism derangements and emerges as a possible risk factor underlying the negative cardiovascular outcome in CKD patients. However, its contribution in non-CKD individuals is less clear. This cross-sectional study investigated the associations between FGF23 and mineral metabolism parameters and with carotid atherosclerosis in a population at high cardiovascular risk with preserved renal function. METHODS We employed 939 subjects with coronary heart disease enrolled in the CORDIOPREV study (mean eGFR=93.0 ± 0.7 ml/min/1.73 m2 and median FGF23=44.9 (IQR=13.1) pg/ml), in which intima-media thickness of both common carotid arteries (IMT-CC) was measured. RESULTS Adjusted for anthropometric factors, FGF23 associated positively with creatinine, phosphate, calcium and 25(OH)-vitaminD and negatively with eGFR and calcitriol. In multivariable-adjusted models all of them were independent contributors to FGF23 levels. FGF23 showed a positive relationship with IMT-CC; both the higher third and fourth quartiles associated significantly with IMT-CC (Beta= 0.135 and 0.187, respectively) and after additional adjustment for established cardiovascular risk factors and morbidities FGF23 remained as a significant contributor to IMT-CC. Logistic regression analysis confirmed its predictive ability to differentiate patients at higher atherosclerotic risk defined by an IMT-CC≥0.7 mm (OR for FGF23 quartiles 3 and 4 vs. 1: 1.860; 95%CI 1.209-2.862 and 2.114; 95%CI 1.339-3.337, respectively). CONCLUSION Even in the setting of a normally functioning phosphate-FGF23-calcitriol system, FGF23 independently associated with IMT-CC, a surrogate of atherosclerotic vascular dysfunction. This supports the notion of FGF23 as a predictor of cardiovascular risk independent of renal failure.
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Affiliation(s)
- Maria E Rodríguez-Ortiz
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Reina Sofia University Hospital/University of Cordoba, Spain
| | - Juan F Alcalá-Díaz
- Lipid and Atherosclerosis Unit, Department of Internal Medicine (IMIBIC), Reina Sofia University Hospital/University of Cordoba, Avda. Menéndez Pidal s/n. C.P., 14004 Cordoba, Spain; CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain
| | - Antonio Canalejo
- Department of Integrated Sciences/Centro de investigacion RENSMA, University of Huelva, Spain
| | - José D Torres-Peña
- Lipid and Atherosclerosis Unit, Department of Internal Medicine (IMIBIC), Reina Sofia University Hospital/University of Cordoba, Avda. Menéndez Pidal s/n. C.P., 14004 Cordoba, Spain; CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain
| | - Francisco Gómez-Delgado
- Lipid and Atherosclerosis Unit, Department of Internal Medicine (IMIBIC), Reina Sofia University Hospital/University of Cordoba, Avda. Menéndez Pidal s/n. C.P., 14004 Cordoba, Spain; CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain
| | - Juan R Muñoz-Castañeda
- Unidad de Gestión Clinica Nefrología, Instituto Maimonides de Investigacion Biomédica de Córdoba (IMIBIC), Reina Sofia University Hospital/University of Cordoba, Spain
| | - Javier Delgado-Lista
- Lipid and Atherosclerosis Unit, Department of Internal Medicine (IMIBIC), Reina Sofia University Hospital/University of Cordoba, Avda. Menéndez Pidal s/n. C.P., 14004 Cordoba, Spain; CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain
| | - Mariano Rodríguez
- Unidad de Gestión Clinica Nefrología, Instituto Maimonides de Investigacion Biomédica de Córdoba (IMIBIC), Reina Sofia University Hospital/University of Cordoba, Spain
| | - José López-Miranda
- Lipid and Atherosclerosis Unit, Department of Internal Medicine (IMIBIC), Reina Sofia University Hospital/University of Cordoba, Avda. Menéndez Pidal s/n. C.P., 14004 Cordoba, Spain; CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain.
| | - Yolanda Almadén
- Unidad de Gestión Clinica Medicina Interna, Instituto de Biomedicina de Córdoba (IMIBIC), Hospital Universitario Reina Sofía de Córdoba/Universidad de Córdoba, Spain; CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Spain.
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Bouma-de Krijger A, de Roij van Zuijdewijn CLM, Nubé MJ, Grooteman MPC, Vervloet MG. Change in FGF23 concentration over time and its association with all-cause mortality in patients treated with haemodialysis or haemodiafiltration. Clin Kidney J 2020; 14:891-897. [PMID: 33777372 PMCID: PMC7986440 DOI: 10.1093/ckj/sfaa028] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 12/26/2019] [Indexed: 12/18/2022] Open
Abstract
Background Previous studies in patients on haemodialysis (HD) have shown an association of fibroblast growth factor 23 (FGF23) with all-cause mortality. As of yet, the result of FGF23 lowering on mortality is unknown in this population. Methods FGF23 was measured in a subset of 404 patients from the Dutch CONvective TRansport STudy (CONTRAST study) [a randomized trial in prevalent dialysis patients comparing HD and haemodiafiltration (HDF) with clinical outcome] at baseline and Months 6 and 12. A substantial decline of FGF23 change over time was anticipated in patients randomized to HDF since HDF induces higher dialytic clearance of FGF23. The associations of both baseline FGF23 and 6-months change in FGF23 with all-cause mortality were analysed. In addition, the difference in FGF23 change between HD and HDF was explored. Furthermore, the role of dialysis modality in the association between FGF23 change and outcome was analysed. Results No association was observed between quartiles of baseline FGF23 and all-cause mortality. Over 6 months, FGF23 declined in patients on HDF, whereas FGF23 remained stable in patients on HD. A decrease in FGF23 was not associated with improved survival compared with a stable FGF23 concentration. However, increasing FGF23 was associated with a significantly higher mortality risk, both in crude and fully adjusted models [hazard ratio 2.01 (95% confidence interval 1.30–3.09)]. Conclusion Whereas no association between a single value of FGF23 and all-cause mortality was found, increasing FGF23 concentrations did identify patients at risk for mortality. Since lowering FGF23 did not improve outcome, this study found no argument for therapeutically lowering FGF23.
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Affiliation(s)
- Annet Bouma-de Krijger
- Department of Nephrology, Amsterdam University Medical Center, VU University Amsterdam, Amsterdam, The Netherlands.,Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Camiel L M de Roij van Zuijdewijn
- Department of Nephrology, Amsterdam University Medical Center, VU University Amsterdam, Amsterdam, The Netherlands.,Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Menso J Nubé
- Department of Nephrology, Amsterdam University Medical Center, VU University Amsterdam, Amsterdam, The Netherlands.,Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Muriel P C Grooteman
- Department of Nephrology, Amsterdam University Medical Center, VU University Amsterdam, Amsterdam, The Netherlands.,Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Marc G Vervloet
- Department of Nephrology, Amsterdam University Medical Center, VU University Amsterdam, Amsterdam, The Netherlands.,Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, The Netherlands
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COBAN M, YİLMAZ U, DOLU S, ASİLTURK E, SOZER Y, EROL B, ELLİDAG HY. Intact Fibroblast Growth Factor 23 and Peripheral Vascular Complications in Patients on Hemodialysis. DICLE MEDICAL JOURNAL 2020. [DOI: 10.5798/dicletip.706013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Lacroix JS, Urena-Torres P. Potentielle application de l’axe fibroblast growth factor 23-Klotho dans la maladie rénale chronique. Nephrol Ther 2020; 16:83-92. [DOI: 10.1016/j.nephro.2019.05.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 05/19/2019] [Indexed: 12/17/2022]
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Jagieła J, Bartnicki P, Rysz J. Selected cardiovascular risk factors in early stages of chronic kidney disease. Int Urol Nephrol 2020; 52:303-314. [PMID: 31955363 DOI: 10.1007/s11255-019-02349-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 11/24/2019] [Indexed: 02/07/2023]
Abstract
Cardiovascular diseases, including hypertension, congestive heart failure, myocardial infarction, stroke and atherosclerosis, are common in patients with chronic kidney disease. Aside from the standard biomarkers, measured to determine cardiovascular risk, new ones have emerged: markers of oxidative stress, apoptosis, inflammation, vascular endothelium dysfunction, atherosclerosis, organ calcification and fibrosis. Unfortunately, their utility for routine clinical application remains to be elucidated. A causal relationship between new markers and cardiovascular diseases in patients with chronic kidney disease remains to be established. First of all, there is a lack of large, randomized trials. Moreover, most studies focus on patients with end-stage renal disease as well as on dialysed patients. In such patients, cardiovascular diseases are already present and advanced while early detection of cardiovascular disease risk factor in patients with early-stages of chronic kidney disease would allow more precise prognosis and, as a result, changes in treatment algorithm. In this article, we conduct a comprehensive review of literature for publications relating to cardiovascular risk factors in patients with early-stages of chronic kidney disease. Overall, there are many encouraging advances in detection of cardiovascular risk factors that are making the future more promising for patients suffering from chronic kidney disease.
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Affiliation(s)
- Joanna Jagieła
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Żeromskiego 113, 90-549, Lodz, Poland.
| | - Piotr Bartnicki
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Żeromskiego 113, 90-549, Lodz, Poland
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Żeromskiego 113, 90-549, Lodz, Poland
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Omede F, Zhang S, Johnson C, Daniel E, Zhang Y, Fields TA, Boulanger J, Liu S, Ahmed I, Umar S, Wallace DP, Stubbs JR. Dietary phosphate restriction attenuates polycystic kidney disease in mice. Am J Physiol Renal Physiol 2020; 318:F35-F42. [DOI: 10.1152/ajprenal.00282.2019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Studies in rodents with reduced nephron mass have suggested a strong positive correlation between dietary phosphate consumption and CKD progression. Prior work by our group demonstrated that dietary phosphate restriction can prevent tubular injury and microcyst formation in rodents with glomerulonephritis. Tubular injury and cystic dilation of tubules are key contributors to kidney function decline in polycystic kidney disease (PKD). Here, we determined whether dietary phosphate restriction slows renal cyst growth and fibrosis in a mouse model of PKD. Pcy/pcy mice received a normal phosphate (0.54%) or a phosphate-restricted (0.02%) diet ( n = 10/group) from 7 to 20 wk of age. All of the other major dietary constituents, including protein source and content, were comparable between the two diets. At 20 wk, body weight, kidney weight-to-body weight ratio (KW/BW), cystic area, cyst number, and kidney fibrosis were quantified. Pcy/pcy mice fed a phosphate-restricted diet had lower serum phosphate, fibroblast growth factor 23, and parathyroid hormone levels, along with elevated serum calcium levels and increased kidney Klotho gene expression compared with mice that consumed the control diet. Dietary phosphate restriction resulted in a 25% lower KW/BW ratio and reduced the cyst number, cystic index, and gene expression for the tubular injury markers neutrophil gelatinase-associated lipocalin and interleukin-18. Mice fed the phosphate-restricted diet exhibited lower kidney expression for pathways involved in collagen deposition and myofibroblast activation (collagen type I-α1, phosphorylated SMAD3, and α-smooth muscle actin); however, histological differences in kidney fibrosis were not appreciated. Dietary phosphate restriction slows cystogenesis and inhibits the activation of key pathways in the generation of kidney fibrosis in PKD mice.
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Affiliation(s)
- Faith Omede
- The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas
| | - Shiqin Zhang
- The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas
| | - Cassandra Johnson
- The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas
| | - Emily Daniel
- The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas
| | - Yan Zhang
- The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas
| | - Timothy A. Fields
- The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas
- Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas
| | | | | | - Ishfaq Ahmed
- Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas
| | - Shahid Umar
- Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas
| | - Darren Paul Wallace
- The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas
- Department of Internal Medicine, Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, Kansas
| | - Jason R. Stubbs
- The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas
- Department of Internal Medicine, Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, Kansas
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Elsalam MA, El-Abden MZ, Mahmoud E, Zahab ZA, Ahmed H. Correlation between serum sclerostin level and bone density status in children on regular hemodialysis. SAUDI JOURNAL OF KIDNEY DISEASES AND TRANSPLANTATION 2019; 30:1022-1031. [PMID: 31696839 DOI: 10.4103/1319-2442.270256] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Bone disease is frequently observed in chronic kidney disease (CKD) and increases a patient's risk for fracture. Sclerostin is an osteocyte-derived negative regulator of bone formation. We aimed to assess serum sclerostin level as a bone marker in children with CKD on regular hemodialysis (HD) and detect the association between this and bone density status. This cross-sectional comparative study was conducted on 25 children with CKD on HD and 25 age- and sex-matched healthy children, as controls. Their ages ranged from 4 to 18 years. Serum sclerostin levels were measured and dual-energy X-ray absorptiometry scan was performed in the same line with the traditional bone markers. There was a significant increase in serum sclerostin level in patients (1.754 ± 1.31 ng/mL) compared to controls (0.290 ± 0.074 ng/mL) with P = 0.001. Nine patients (36%) had low bone mineral density (BMD) with z score under -2.0, eight of whom had low BMD in both the neck of femur and lumbar spines. There was a significant increase in serum sclerostin levels in the patient-group with low BMD (2.38 ± 0.85 ng/mL) compared with patients with normal BMD (1.4 ± 0.98 ng/mL) (P = 0.001). A significant positive correlation was found between serum sclerostin level and alkaline phosphtase, parathormone with negative correlation with serum calcium. Sclerostin was 100% specific and sensitive in predicting CKD-mineral and bone disorder. Elevated sclerostin levels were consistent with low BMD and appear to be an independent predictor of reduced BMD in children on regular HD.
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Affiliation(s)
- Manal Abd Elsalam
- Department of Pediatrics, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Maha Zein El-Abden
- Department of Pediatrics, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Eman Mahmoud
- Department of Endocrinology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Zakia Abo Zahab
- Department of Clinical Pathology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Heba Ahmed
- Department of Pediatrics, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
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Vogt I, Haffner D, Leifheit-Nestler M. FGF23 and Phosphate-Cardiovascular Toxins in CKD. Toxins (Basel) 2019; 11:E647. [PMID: 31698866 PMCID: PMC6891626 DOI: 10.3390/toxins11110647] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 10/30/2019] [Accepted: 11/01/2019] [Indexed: 12/11/2022] Open
Abstract
Elevated levels of fibroblast growth factor 23 (FGF23) and phosphate are highly associated with increased cardiovascular disease and mortality in patients suffering from chronic kidney disease (CKD). As the kidney function declines, serum phosphate levels rise and subsequently induce the secretion of the phosphaturic hormone FGF23. In early stages of CKD, FGF23 prevents the increase of serum phosphate levels and thereby attenuates phosphate-induced vascular calcification, whereas in end-stage kidney disease, FGF23 fails to maintain phosphate homeostasis. Both hyperphosphatemia and elevated FGF23 levels promote the development of hypertension, vascular calcification, and left ventricular hypertrophy by distinct mechanisms. Therefore, FGF23 and phosphate are considered promising therapeutic targets to improve the cardiovascular outcome in CKD patients. Previous therapeutic strategies are based on dietary and pharmacological reduction of serum phosphate, and consequently FGF23 levels. However, clinical trials proving the effects on the cardiovascular outcome are lacking. Recent publications provide evidence for new promising therapeutic interventions, such as magnesium supplementation and direct targeting of phosphate and FGF receptors to prevent toxicity of FGF23 and hyperphosphatemia in CKD patients.
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Affiliation(s)
| | | | - Maren Leifheit-Nestler
- Department of Pediatric Kidney, Liver and Metabolic Diseases Hannover Medical School, 30625 Hannover, Germany; (I.V.); (D.H.)
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Pickup L, Radhakrishnan A, Townend JN, Ferro CJ. Arterial stiffness in chronic kidney disease. Curr Opin Nephrol Hypertens 2019; 28:527-536. [DOI: 10.1097/mnh.0000000000000535] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Donate-Correa J, Martín-Núñez E, Hernández-Carballo C, Ferri C, Tagua VG, Delgado-Molinos A, López-Castillo Á, Rodríguez-Ramos S, Cerro-López P, López-Tarruella VC, Felipe-García R, Arévalo-Gomez MA, Pérez-Delgado N, Mora-Fernández C, Navarro-González JF. Fibroblast growth factor 23 expression in human calcified vascular tissues. Aging (Albany NY) 2019; 11:7899-7913. [PMID: 31542779 PMCID: PMC6781973 DOI: 10.18632/aging.102297] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 09/14/2019] [Indexed: 12/20/2022]
Abstract
Vascular calcification is a major risk for cardiovascular disease and implies the transformation of smooth muscle cells to an osteoblastic phenotype as a consequence of dysregulation of calcium and phosphate metabolism. Fibroblast growth factor (FGF) 23 is the most potent phosphate regulator. Observational studies suggest that high levels of FGF23 are related to cardiovascular morbidity and mortality. In this work, we determined the levels of both the intact and the carboxi-terminal fragments of circulating FGF23 in 133 patients with established cardiovascular disease, the expression of FGF23, its receptors 1 and 3, and its co-receptor Klotho in vascular fragments of aorta, carotid and femoral in 43 out of this group of patients, and in a control group of 20 organ donors. Patients with atherosclerosis and vascular calcification presented increased levels of FGF23 respect to the control group. Vascular immunoreactivity for FGF23 was also significantly increased in patients with vascular calcification as compared to patients without calcification and to controls. Finally, gene expression of FGF23 and RUNX2 were also higher and directly related in vascular samples with calcification. Conversely, expression of Klotho was reduced in patients with cardiovascular disease when comparing to controls. In conclusion, our findings link the calcification of the vascular tissue with the expression of FGF23 in the vessels and with the elevation of circulating levels this hormone.
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Affiliation(s)
- Javier Donate-Correa
- Research Unit, University Hospital Nuestra Señora de Candelaria (UHNSC), Santa Cruz de Tenerife, Spain
| | - Ernesto Martín-Núñez
- Research Unit, University Hospital Nuestra Señora de Candelaria (UHNSC), Santa Cruz de Tenerife, Spain
- Doctoral and Graduate School, University of La Laguna, San Cristóbal de La Laguna, Tenerife, Spain
| | - Carolina Hernández-Carballo
- Research Unit, University Hospital Nuestra Señora de Candelaria (UHNSC), Santa Cruz de Tenerife, Spain
- Doctoral and Graduate School, University of La Laguna, San Cristóbal de La Laguna, Tenerife, Spain
| | - Carla Ferri
- Research Unit, University Hospital Nuestra Señora de Candelaria (UHNSC), Santa Cruz de Tenerife, Spain
- Doctoral and Graduate School, University of La Laguna, San Cristóbal de La Laguna, Tenerife, Spain
| | - Víctor G. Tagua
- Research Unit, University Hospital Nuestra Señora de Candelaria (UHNSC), Santa Cruz de Tenerife, Spain
| | | | | | | | | | | | | | | | | | - Carmen Mora-Fernández
- Research Unit, University Hospital Nuestra Señora de Candelaria (UHNSC), Santa Cruz de Tenerife, Spain
| | - Juan F. Navarro-González
- Research Unit, University Hospital Nuestra Señora de Candelaria (UHNSC), Santa Cruz de Tenerife, Spain
- Nephrology Service, UHNSC, Santa Cruz de Tenerife, Spain
- Biomedical Technologies Institute, University of La Laguna, Tenerife, Spain
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Edmonston D, Wojdyla D, Mehta R, Cai X, Lora C, Cohen D, Townsend RR, He J, Go AS, Kusek J, Weir MR, Isakova T, Pencina M, Wolf M. Single Measurements of Carboxy-Terminal Fibroblast Growth Factor 23 and Clinical Risk Prediction of Adverse Outcomes in CKD. Am J Kidney Dis 2019; 74:771-781. [PMID: 31445926 DOI: 10.1053/j.ajkd.2019.05.026] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Accepted: 05/13/2019] [Indexed: 01/02/2023]
Abstract
RATIONALE & OBJECTIVE An elevated fibroblast growth factor 23 (FGF-23) level is independently associated with adverse outcomes in populations with chronic kidney disease, but it is unknown whether FGF-23 testing can improve clinical risk prediction in individuals. STUDY DESIGN Prospective cohort study. SETTING & PARTICIPANTS Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study (n = 3,789). EXPOSURE Baseline carboxy-terminal FGF-23 (cFGF-23) level. OUTCOMES All-cause and cardiovascular (CV) mortality, incident end-stage renal disease (ESRD), heart failure (HF) admission, and atherosclerotic events at 3, 5, and 8 years. ANALYTICAL APPROACH We assessed changes in model performance by change in area under the receiver operating characteristic curve (ΔAUC), integrated discrimination improvement (IDI), relative IDI, and net reclassification index (NRI) above standard clinical factors. We performed sensitivity analyses, including an additional model comparing the addition of phosphate rather than cFGF-23 level and repeating our analyses using an internal cross-validation cohort. RESULTS Addition of a single baseline value of cFGF-23 to a base prediction model improved prediction of all-cause mortality (ΔAUC, 0.017 [95% CI, 0.001-0.033]; IDI, 0.021 [95% CI, 0.006-0.036]; relative IDI, 32.7% [95% CI, 8.5%-56.9%]), and HF admission (ΔAUC, 0.008 [95% CI, 0.0004-0.016]; IDI, 0.019 [95% CI, 0.004-0.034]; relative IDI, 10.0% [95% CI, 1.8%-18.3%]), but not CV mortality, ESRD, or atherosclerotic events at 3 years of follow-up. The NRI did not reach statistical significance for any of the 3-year outcomes. The incremental predictive utility of cFGF-23 level diminished in analyses of the 5- and 8-year outcomes. The cFGF-23 models outperformed the phosphate model for each outcome. LIMITATIONS Power to detect increased CV mortality likely limited by low event rate. The NRI is not generalizable without accepted prespecified risk thresholds. CONCLUSIONS Among individuals with CKD, single measurements of cFGF-23 improve prediction of risks for all-cause mortality and HF admission but not CV mortality, ESRD, or atherosclerotic events. Future studies should evaluate the predictive utility of repeated cFGF-23 testing.
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Affiliation(s)
- Daniel Edmonston
- Division of Nephrology, Department of Medicine, Durham, NC; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC
| | - Daniel Wojdyla
- Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC
| | - Rupal Mehta
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL; Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Xuan Cai
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Claudia Lora
- Department of Medicine, University of Illinois at Chicago, Chicago, IL
| | - Debbie Cohen
- Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Raymond R Townsend
- Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Jiang He
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA
| | - Alan S Go
- Kaiser Permanente Northern California Division of Research, Oakland, CA
| | | | - Matthew R Weir
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
| | - Tamara Isakova
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL; Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Michael Pencina
- Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC; Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC
| | - Myles Wolf
- Division of Nephrology, Department of Medicine, Durham, NC; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC.
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Mizuiri S, Nishizawa Y, Yamashita K, Naito T, Ono K, Tanji C, Usui K, Doi S, Masaki T, Shigemoto K. Hypomagnesemia is not an independent risk factor for mortality in Japanese maintenance hemodialysis patients. Int Urol Nephrol 2019; 51:1043-1052. [PMID: 30977017 PMCID: PMC6543028 DOI: 10.1007/s11255-019-02073-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 01/03/2019] [Indexed: 11/25/2022]
Abstract
PURPOSE It is unclear whether hypomagnesemia is an independent risk factor or innocent bystander for mortality in maintenance hemodialysis (MHD) patients. Thus, we studied associations between hypomagnesemia and all-cause as well as cardiovascular (CV) mortality in MHD patients. METHODS Baseline clinical characteristics and coronary artery calcium score (CACS) of 353 Japanese MHD patients were reviewed. Three-year survival rate and mortality risk factors were assessed. RESULTS Median (interquartile range) age, dialysis vintage, serum magnesium (Mg), serum albumin and CACS of the subjects were 68 (60-78) years, 75 (32-151) months, 2.4 (2.2-2.7) mg/dl, 3.6 (3.3-3.8) g/dl, and 1181 (278-3190), respectively. During the 3-year period, 91 patients died. Kaplan-Meier overall 3-year survival rates were 59.0% in in patients with Mg < 2.4 mg/dl (n = 136) and 82.3% in patients with Mg ≥ 2.4 mg/dl (n = 217), (P < 0.0001). In Cox regression models not incorporating serum albumin, Mg < 2.4 mg/dl was significantly associated with 3-year all-cause death, independent of age, dialysis vintage, average ultrafiltration, Log (CACS + 1), warfarin use, serum potassium, high-sensitivity C-reactive protein (hsCRP), phosphate, uric acid, and intact parathyroid hormone [Hazard ratio (HR) 95% confidence interval (CI): 2.82 (1.31-6.29), P = 0.0078], and CV death, independent of age, dialysis vintage, Log (CACS + 1), warfarin use, serum hsCRP, and uric acid [HR (95% CI): 4.47 (1.45-16.76), P = 0.0086]. Nevertheless, associations of Mg < 2.4 mg/dl with all-cause and CV mortality were all absent in models that included serum albumin. CONCLUSIONS Hypomagnesemia is not an independent risk factor for mortality but is associated with malnutrition in MHD patients.
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Affiliation(s)
- Sonoo Mizuiri
- Division of Nephrology, Ichiyokai Harada Hospital, 7-10 Kairoyama-cho, Saeki-ku, Hiroshima, 731-5134, Japan.
| | - Yoshiko Nishizawa
- Division of Nephrology, Ichiyokai Harada Hospital, 7-10 Kairoyama-cho, Saeki-ku, Hiroshima, 731-5134, Japan
| | - Kazuomi Yamashita
- Division of Nephrology, Ichiyokai Harada Hospital, 7-10 Kairoyama-cho, Saeki-ku, Hiroshima, 731-5134, Japan
| | - Takayuki Naito
- Division of Nephrology, Ichiyokai Harada Hospital, 7-10 Kairoyama-cho, Saeki-ku, Hiroshima, 731-5134, Japan
| | - Kyoka Ono
- Division of Nephrology, Ichiyokai Harada Hospital, 7-10 Kairoyama-cho, Saeki-ku, Hiroshima, 731-5134, Japan
| | - Chie Tanji
- Ichiyokai Ichiyokai Clinic, 10-3 Asahien, Saeki-ku, Hiroshima, 731-5133, Japan
| | - Koji Usui
- Ichiyokai Ichiyokai Clinic, 10-3 Asahien, Saeki-ku, Hiroshima, 731-5133, Japan
| | - Shigehiro Doi
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi Minami-ku, Hiroshima, 734-8551, Japan
| | - Takao Masaki
- Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi Minami-ku, Hiroshima, 734-8551, Japan
| | - Kenichiro Shigemoto
- Division of Nephrology, Ichiyokai Harada Hospital, 7-10 Kairoyama-cho, Saeki-ku, Hiroshima, 731-5134, Japan
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Toxines urémiques de moyen poids moléculaire : un véritable regain d’intérêt. Nephrol Ther 2019; 15:82-90. [DOI: 10.1016/j.nephro.2018.09.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 09/02/2018] [Indexed: 01/20/2023]
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Bouma-de Krijger A, van Ittersum FJ, Hoekstra T, Ter Wee PM, Vervloet MG. Short-term effects of sevelamer-carbonate on fibroblast growth factor 23 and pulse wave velocity in patients with normophosphataemic chronic kidney disease Stage 3. Clin Kidney J 2019; 12:678-685. [PMID: 31584563 PMCID: PMC6768309 DOI: 10.1093/ckj/sfz027] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Indexed: 12/25/2022] Open
Abstract
Background High concentrations of both phosphate and fibroblast growth factor 23 (FGF23) observed in chronic kidney disease (CKD) are associated with an increased risk of cardiovascular morbidity and mortality. Pulse wave velocity (PWV) is a surrogate marker for cardiovascular events and all-cause mortality. It is not known whether a reduction of FGF23 or phosphate alters cardiovascular risk. Sevelamer has shown to have the ability to reduce both phosphate and FGF23 concentrations. Furthermore, reduction of PWV is reported with sevelamer use as well, but it is unclear if this is mediated by decline of phosphate or FGF23. We investigated if sevelamer induced a decline in PWV and if this was associated with a reduction in FGF23. Methods In all, 24 normophosphataemic CKD Stage 3 patients started treatment with a fixed dose of sevelamer-carbonate (Renvela®) 2.4 g twice daily, with their usual diet for 8 weeks in a single-arm study. PWV was measured and blood samples were obtained before, during and after washout of treatment with sevelamer. Vascular calcification was quantified using the Kauppila Index (KI). The primary outcome was the change of PWV from baseline to 8 weeks of treatment and the secondary endpoint was the difference of FGF23 following treatment with sevelamer. One of the linear mixed models was used to analyse the association between treatment and outcome. Mediation analysis was performed as a sensitivity analysis. The study was registered in the Dutch trial register (http://www.trialregister.nl: NTR2383). Results A total of 18 patients completed 8 weeks of treatment with sevelamer and were analysed. Overall, treatment with sevelamer did not induce a significant reduction of PWV (β = −0.36, P = 0.12). However, in patients with less vascular calcification (lower KI score), there was a statistically significant reduction of PWV, adjusted for mean arterial pressure, after treatment (β = 0.63, P = 0.02). Addition of FGF23 to the model did not alter this association. Mediation analysis yielded similar results. FGF23 did not decrease during treatment with sevelamer. Conclusion In this short-term pilot study in normophosphataemic CKD patients, treatment with sevelamer did not improve PWV. In subgroup analysis, however, PWV improved in patients with no or limited abdominal aorta calcifications. This was not associated with a decline of FGF23.
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Affiliation(s)
- Annet Bouma-de Krijger
- Department of Nephrology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Frans J van Ittersum
- Department of Nephrology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.,Amsterdam Cardiovascular Sciences Institute (ACS), O2
- Building for Human Life Sciences, Amsterdam, The Netherlands
| | - Tiny Hoekstra
- Department of Nephrology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Pieter M Ter Wee
- Department of Nephrology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Marc G Vervloet
- Department of Nephrology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.,Amsterdam Cardiovascular Sciences Institute (ACS), O2
- Building for Human Life Sciences, Amsterdam, The Netherlands
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Dual Roles of the Mineral Metabolism Disorders Biomarkers in Prevalent Hemodilysis Patients: In Renal Bone Disease and in Vascular Calcification. J Med Biochem 2019; 38:134-144. [PMID: 30867641 PMCID: PMC6411002 DOI: 10.2478/jomb-2018-0026] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 06/16/2018] [Indexed: 12/21/2022] Open
Abstract
Background Vascular calcification (VC) is highly prevalent in dialysis (HD) patients, and its mechanism is multifactorial. Most likely that systemic or local inhibitory factor is overwhelmed by promoters of VC in these patients. VC increased arterial stiffness, and left ventricular hypertrophy. Thus, the present study aimed to investigate the association of VC and myocardial remodeling and to analyze their relationship with VC promoters (fibroblast growth factor 23-FGF23, Klotho, intact parathormon-iPTH, vitamin D) in 56 prevalent HD patients (median values: age 54 yrs, HD vintage 82 months). Methods Besides routine laboratory analyzes, serum levels of FGF 23, soluble Klotho, iPTH, 1,25-dihydroxyvitamin D3; pulse wave velocity (PWV); left ventricular (LV) mass by ultrasound; and VCs score by Adragao method were measured. Results VC was found in 60% and LV concentric or eccentric hypertrophy in 50% patients. Dialysis vintage (OR 1.025, 95%CI 1.007–1.044, p=0.006) FGF23 (OR 1.006, 95% CI 0.992–1.012, p=0.029) and serum magnesium (OR 0.000, 95%CI 0.000–0.214, p=0.04) were associated with VC. Changes in myocardial geometry was associated with male sex (beta=-0.273, 95% CI -23.967 1.513, p=0.027), iPTH (beta 0.029, 95%CI -0.059–0.001, p=0.027) and vitamin D treatment (beta 25.49, 95%CI 11.325–39.667, p=0.001). Also, patients with the more widespread VC had the highest LV remodeling categories. PWV was associated patient’s age, cholesterol, diastolic blood pressure, LV mass (positively) and serum calcium (negatively), indicating potential link with atherosclerotic risk. Conclusions Despite to different risk factors for VC and myocardial remodeling, obtained results could indicate that risk factors intertwine in long-term treatment of HD patients and therefore careful and continuous correction of mineral metabolism disorders is undoubtedly of the utmost importance.
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Gao S, Xu J, Zhang S, Jin J. Meta-Analysis of the Association between Fibroblast Growth Factor 23 and Mortality and Cardiovascular Events in Hemodialysis Patients. Blood Purif 2019; 47 Suppl 1:24-30. [PMID: 30699419 DOI: 10.1159/000496220] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
INTRODUCTION This study was conducted to ensure the correlation between fibroblast growth factor 23 (FGF23) and death and cardiovascular events in hemodialysis patients. METHODS We conducted a literature search of PubMed database to April 2018 for relevant articles that reported the association between FGF23 and risk of all-cause mortality and cardiovascular disease (CVD) events. The meta-analysis was performed using the Revman 5.3 software. RESULTS A total of 7 articles were included, and all reported mortality in hemodialysis patients, and 3 reported cardiovascular events in hemodialysis patients. Since the current reagent can detect C-terminal FGF23 (cFGF23) and intact-FGF23 (iFGF23), we discuss the association between cFGF23 and iFGF23 and death and cardiovascular events in hemodialysis patients. The correlation between serum iFGF23 levels and death in hemodialysis patients: high levels of iFGF23 vs. low levels of iFGF23: RR 1.14, 95% CI (1.01-1.30), p = 0.04 (I2 = 0%, p = 0.38). The correlation between serum C-terminal levels and death in hemodialysis patients: high levels of cFGF23 versus low levels of cFGF23: RR 1.39, 95% CI (1.21-1.59), p < 0.001 (I2 = 2%, p = 0.38). The correlation of serum iFGF23 levels with cardiovascular events: high levels of iFGF23 versus low levels of iFGF23: RR 1.21, 95% CI (1.13-1.30), p < 0.001 (I2 = 0%, p = 0.49). A paper has reported the association between cFGF23 and CVD events, so we did not conduct meta-analysis. CONCLUSIONS Elevated serum FGF23 levels are positively associated with all-cause mortality and cardiovascular events in hemodialysis patients, with a 14 or 39% increase in all-cause mortality and a 21% increased risk of cardiovascular events.
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Affiliation(s)
- Shaohui Gao
- Departments of Nephrology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jinsheng Xu
- Departments of Nephrology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China,
| | - Shenglei Zhang
- Departments of Nephrology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jingjing Jin
- Departments of Nephrology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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