Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor–dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF–receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.
Christian Faul, Ansel P. Amaral, Behzad Oskouei, Ming-Chang Hu, Alexis Sloan, Tamara Isakova, Orlando M. Gutiérrez, Robier Aguillon-Prada, Joy Lincoln, Joshua M. Hare, Peter Mundel, Azorides Morales, Julia Scialla, Michael Fischer, Elsayed Z. Soliman, Jing Chen, Alan S. Go, Sylvia E. Rosas, Lisa Nessel, Raymond R. Townsend, Harold I. Feldman, Martin St. John Sutton, Akinlolu Ojo, Crystal Gadegbeku, Giovana Seno Di Marco, Stefan Reuter, Dominik Kentrup, Klaus Tiemann, Marcus Brand, Joseph A. Hill, Orson W. Moe, Makoto Kuro-o, John W. Kusek, Martin G. Keane, Myles Wolf
Title and authors | Publication | Year |
---|---|---|
HERC1 deficiency causes osteopenia through transcriptional program dysregulation during bone remodeling
Pedrazza L, Martinez-Martinez A, Sánchez-de-Diego C, Valer JA, Pimenta-Lopes C, Sala-Gaston J, Szpak M, Tyler-Smith C, Ventura F, Rosa JL |
Cell Death and Disease | 2023 |
Osteocyte Egln1/Phd2 links oxygen sensing and biomineralization via FGF23
Noonan ML, Ni P, Solis E, Marambio YG, Agoro R, Chu X, Wang Y, Gao H, Xuei X, Clinkenbeard EL, Jiang G, Liu S, Stegen S, Carmeliet G, Thompson WR, Liu Y, Wan J, White KE |
Bone Research | 2023 |
1,25-dihydroxy vitamin D regulates furin-mediated FGF23 cleavage
Han Xie, Isinsu Bastepe, Wen Zhou, Birol Ay, Zara Ceraj, Ignacio Portales, Sherrie Burnett-Bowie, Harald Juppner, Eugene Rhee, Murat Bastepe, Petra Simic |
JCI Insight | 2023 |
Updates in the chronic kidney disease-mineral bone disorder show the role of osteocytic proteins, a potential mechanism of the bone—Vascular paradox, a therapeutic target, and a biomarker
Williams MJ, White SC, Joseph Z, Hruska KA |
Frontiers in physiology | 2023 |
Fibroblast Growth Factor-23 and Risk of Cardiovascular Diseases: a Mendelian Randomization study
Donovan K, Herrington WG, Paré G, Pigeyre M, Haynes R, Sardell R, Butterworth AS, Folkersen L, Gustafsson S, Wang Q, Baigent C, Mälarstig A, Holmes MV, Staplin N |
Clinical journal of the American Society of Nephrology : CJASN | 2023 |
Efficacy of antiresorptive agents bisphosphonates and denosumab in mitigating hypercalcemia and bone loss in primary hyperparathyroidism: A systematic review and meta-analysis
Rajput S, Dutta A, Rajender S, Mithal A, Chattopadhyay N |
Frontiers in Endocrinology | 2023 |
FGF23 in Chronic Kidney Disease: Bridging the Heart and Anemia
Figurek A, Rroji M, Spasovski G |
Cells | 2023 |
Fibroblast growth factor 18 alleviates stress-induced pathological cardiac hypertrophy in male mice
Chen G, An N, Shen J, Chen H, Chen Y, Sun J, Hu Z, Qiu J, Jin C, He S, Mei L, Sui Y, Li W, Chen P, Guan X, Chu M, Wang Y, Jin L, Kim K, Li X, Cong W, Wang X |
Nature Communications | 2023 |
Fibroblast growth factor 23 as a biomarker of right ventricular dysfunction in pulmonary hypertension.
Widmann L, Keranov S, Jafari L, Liebetrau C, Keller T, Troidl C, Kriechbaum S, Voss S, Arsalan M, Richter MJ, Tello K, Gall H, Ghofrani HA, Guth S, Seeger W, Hamm CW, Dörr O, Nef H |
Clinical research in cardiology : official journal of the German Cardiac Society | 2023 |
Fibroblast growth factor 23 in children with or without heart failure: a prospective study.
Elzayat RS, Bahbah WA, Elzaiat RS, Elgazzar BA |
BMJ paediatrics open | 2023 |
Mineral bone disorder in children with chronic kidney disease: Data from the KNOW-Ped CKD (Korean cohort study for outcome in patients with pediatric chronic kidney disease) study
Jung J, Lee KH, Park E, Park YS, Kang HG, Ahn YH, Ha IS, Kim SH, Cho H, Han KH, Cho MH, Choi HJ, Lee JH, Shin JI |
Frontiers in Pediatrics | 2023 |
Indoxyl sulfate induces left ventricular hypertrophy via the AhR-FGF23-FGFR4 signaling pathway
Kishimoto H, Nakano T, Torisu K, Tokumoto M, Uchida Y, Yamada S, Taniguchi M, Kitazono T |
Frontiers in Cardiovascular Medicine | 2023 |
Direct and indirect effects of fibroblast growth factor 23 on the heart
Nakano T, Kishimoto H, Tokumoto M |
Frontiers in Endocrinology | 2023 |
Roles of PTH and FGF23 in kidney failure: a focus on nonclassical effects.
Komaba H |
Clinical and Experimental Nephrology | 2023 |
Accelerated AGEing: The Impact of Advanced Glycation End Products on the Prognosis of Chronic Kidney Disease
Dozio E, Caldiroli L, Molinari P, Castellano G, Delfrate NW, Romanelli MM, Vettoretti S |
Antioxidants | 2023 |
Zebrafish as a Model of Cardiac Pathology and Toxicity: Spotlight on Uremic Toxins.
Coppola A, Lombari P, Mazzella E, Capolongo G, Simeoni M, Perna AF, Ingrosso D, Borriello M |
International journal of molecular sciences | 2023 |
A potential link between fibroblast growth factor-23 and the progression of AKI to CKD
Lu Y, Xu S, Tang R, Han C, Zheng C |
BMC Nephrology | 2023 |
Crosstalk between bone and muscle in chronic kidney disease.
Wong L, McMahon LP |
Frontiers in Endocrinology | 2023 |
Mineral Metabolism in Children: Interrelation between Vitamin D and FGF23
Pons-Belda OD, Alonso-Álvarez MA, González-Rodríguez JD, Mantecón-Fernández L, Santos-Rodríguez F |
International journal of molecular sciences | 2023 |
Vitamin D and Chronic Kidney Disease Association with Mineral and Bone Disorder: An Appraisal of Tangled Guidelines
Bover J, Massó E, Gifre L, Alfieri C, Soler-Majoral J, Fusaro M, Calabia J, Rodríguez-Pena R, Rodríguez-Chitiva N, López-Báez V, Sánchez-Baya M, da Silva I, Aguilar A, Bustos MC, Rodrigues N, Chávez-Iñiguez JS, Romero-González G, Valdivielso JM, Molina P, Górriz JL |
Nutrients | 2023 |
The role of Klotho and FGF23 in cardiovascular outcomes of diabetic patients with chronic limb threatening ischemia: a prospective study.
Biscetti F, Rando MM, Cecchini AL, Nicolazzi MA, Rossini E, Angelini F, Iezzi R, Eraso LH, Dimuzio PJ, Pitocco D, Gasbarrini A, Massetti M, Flex A |
Scientific Reports | 2023 |
Relationship of Fibroblast Growth Factor 23 With Hospitalization for Heart Failure and Cardiovascular Outcomes in Patients Undergoing Cardiac Surgery
Hofer F, Hammer A, Pailer U, Koller L, Kazem N, Steinacher E, Steinlechner B, Andreas M, Laufer G, Wojta J, Zelniker TA, Hengstenberg C, Niessner A, Sulzgruber P |
Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease | 2023 |
Correlation of Serum FGF23 and Chronic Kidney Disease-Mineral and Bone Abnormality Markers With Cardiac Structure Changes in Maintenance Hemodialysis Patients
Zeng D, Zha A, Lei Y, Yu Z, Cao R, Li L, Song Z, Li W, Li Y, Liu H, Huang S, Dong X, Krämer B, Hocher B, Yin L, Yun C, Morgera S, Guan B, Meng Y, Liu F, Hu B, Luan S |
Evidence-based complementary and alternative medicine : eCAM | 2023 |
Different Efficacy of Burosumab on Physical Performance and Serum Phosphate in Adult Patients with X-Linked Hyphophosphatemic Rickets during the First Six-Month of Treatment.
Arcidiacono T, Foligno NE, Brioni E, Bologna A, Weber G, Mora S, Pitea M, Vitale C, Vezzoli G |
Journal of Clinical Medicine | 2023 |
The Association of Leptin with Left Ventricular Hypertrophy in End-Stage Kidney Disease Patients on Dialysis
Coimbra S, Catarino C, Sameiro Faria M, Nunes JP, Rocha S, Valente MJ, Rocha-Pereira P, Bronze-da-Rocha E, Bettencourt N, Beco A, Marques SH, Oliveira JG, Madureira J, Fernandes JC, Miranda V, Belo L, Santos-Silva A |
Biomedicines | 2023 |
Regulation of the Osteocyte Secretome with Aging and Disease.
Kitase Y, Prideaux M |
Calcified Tissue International | 2023 |
Oncostatin M is a regulator of fibroblast growth factor 23 (FGF23) in UMR106 osteoblast-like cells
Münz S, Feger M, Föller M |
Scientific Reports | 2023 |
Fibroblast growth factor 23, klotho and heparin
Thomas SM, Li Q, Faul C |
Current Opinion in Nephrology and Hypertension | 2023 |
Transcriptomic analysis identifies novel candidates in cardiorenal pathology mediated by chronic peritoneal dialysis
Nasci VL, Liu P, Marks AM, Williams AC, Kriegel AJ |
Scientific Reports | 2023 |
Fibroblast Growth Factor 23: Potential Marker of Invisible Heart Damage in Diabetic Population
Kurpas A, Supel K, Wieczorkiewicz P, Bodalska Duleba J, Zielinska M |
Biomedicines | 2023 |
The Importance of the Nephrologist in the Treatment of the Diuretic-Resistant Heart Failure
Pethő ÁG, Tapolyai M, Browne M, Fülöp T, Orosz P, Szabó RP |
Life Sciences | 2023 |
Mendelian randomization and the association of fibroblast growth factor-23 with heart failure with preserved ejection fraction.
Akwo EA, Robinson-Cohen C |
Current Opinion in Nephrology and Hypertension | 2023 |
Fibroblast Growth Factor 23 Bone Regulation and Downstream Hormonal Activity.
Clinkenbeard E |
Calcified Tissue International | 2023 |
FGF23 and klotho at the intersection of kidney and cardiovascular disease.
Edmonston D, Grabner A, Wolf M |
Nature reviews. Cardiology | 2023 |
Bone-derived C-terminal FGF23 cleaved peptides increase iron availability in acute inflammation
Courbon G, Thomas JJ, Martinez-Calle M, Wang X, Spindler J, Von Drasek J, Hunt-Tobey B, Mehta R, Isakova T, Chang W, Creemers JW, Ji P, Martin A, David V |
Blood | 2023 |
Fibroblast growth factor-23 and cardiovascular disease among prevalent hemodialysis patients focusing on residual kidney function
Kee YK, Jeon HJ, Oh J, Cho A, Lee YK, Yoon JW, Kim H, Yoo TH, Shin DH |
Frontiers in Endocrinology | 2023 |
Cardiac Mechanics and Kidney Function Decline in the Cardiovascular Health Study
Mehta R, Buzkova P, Patel H, Cheng J, Kizer JR, Gottdiener JS, Psaty B, Khan SS, Ix JH, Isakova T, Shlipak MG, Bansal N, Shah SJ |
2023 | |
Role of Chronic Kidney Disease (CKD)-Mineral and Bone Disorder (MBD) in the Pathogenesis of Cardiovascular Disease in CKD.
Yamada S, Nakano T |
Journal of Atherosclerosis and Thrombosis | 2023 |
Intact fibroblast growth factor 23 in heart failure with reduced and mildly reduced ejection fraction
Vergaro G, Del Franco A, Aimo A, Gentile F, Castiglione V, Saponaro F, Masotti S, Prontera C, Fusari N, Emdin M, Passino C |
BMC Cardiovascular Disorders | 2023 |
Bone marrow sinusoidal endothelial cells are a site of Fgf23 upregulation in a mouse model of iron deficiency anemia
Li X, Lozovatsky L, Tommasini SM, Fretz J, Finberg KE |
Blood Advances | 2023 |
Cardiovascular complications in chronic kidney disease: a review from the European Renal and Cardiovascular Medicine Working Group of the European Renal Association.
Zoccali C, Mallamaci F, Adamczak M, de Oliveira RB, Massy ZA, Sarafidis P, Agarwal R, Mark PB, Kotanko P, Ferro CJ, Wanner C, Burnier M, Vanholder R, Wiecek A |
Cardiovascular Research | 2023 |
Removal of calciprotein particles from the blood using an adsorption column improves prognosis of hemodialysis miniature pigs
Miura M, Miura Y, Iwazu Y, Mukai H, Sugiura T, Suzuki Y, Kato M, Kano M, Nagata D, Shiizaki K, Kurosu H, Kuro-o M |
Scientific Reports | 2023 |
Klotho/FGF23 Axis Regulates Cardiomyocyte Apoptosis and Cytokine Release through ERK/MAPK Pathway.
Jia Z, Liu Q, Xie Y, Wei J, Sun X, Meng F, Zhao B, Yu Z, Zhao L, Xing Z |
Cardiovascular Toxicology | 2023 |
Assessment and management of heart failure in patients with chronic kidney disease.
Guaricci AI, Sturdà F, Russo R, Basile P, Baggiano A, Mushtaq S, Fusini L, Fazzari F, Bertandino F, Monitillo F, Carella MC, Simonini M, Pontone G, Ciccone MM, Grandaliano G, Vezzoli G, Pesce F |
Heart Failure Reviews | 2023 |
Bibliometric study and review of Klotho research: global characteristics and trends from 2000 to 2023.
Zhang FF, Xu YQ, Xiong JH, Hu JX, Zhu GS, Cheng SM |
International Urology and Nephrology | 2023 |
The effect of intradialytic exercise on calcium, phosphorus and parathyroid hormone: a randomized controlled trial.
Tabibi MA, Wilund KR, Salimian N, Nikbakht S, Soleymany M, Roshanaeian Z, Nazemi F, Ahmadi S |
BMC Nephrology | 2023 |
FGF-23 is a biomarker of RV dysfunction and congestion in patients with HFrEF
Benes J, Kroupova K, Kotrc M, Petrak J, Jarolim P, Novosadova V, Kautzner J, Melenovsky V |
Scientific Reports | 2023 |
MCP1 Inverts the Correlation between FGF23 and Omega 6/3 Ratio: Is It Also True in Renal Transplantation?
Mattinzoli D, Turolo S, Ikehata M, Vettoretti S, Montini G, Agostoni C, Conti C, Benedetti M, Messa P, Alfieri CM, Castellano G |
Journal of Clinical Medicine | 2023 |
Knowledge landscapes and emerging trends of cardiorenal syndrome type 4: a bibliometrics and visual analysis from 2004 to 2022.
Li H, Liu T, Yang L, Ma F, Wang Y, Zhan Y, Mao H |
International Urology and Nephrology | 2023 |
Associations of FGF23 with 10-Year Change in eGFR and UACR and with Incident CKD in the CARDIA Cohort
Sunderraj A, Wong M, Gutiérrez OM, Wolf M, Akhabue E, Carnethon MR, Yancy CW, Isakova T |
2023 | |
Physiopathology of Phosphate Disorders
Portales-Castillo I, Rieg T, Khalid SB, Nigwekar SU, Neyra JA |
2023 | |
Fibroblast Growth Factor 23 and Risk of Heart Failure Subtype: The CRIC (Chronic Renal Insufficiency Cohort) Study
Leidner AS, Cai X, Zelnick LR, Lee J, Bansal N, Pasch A, Kansal M, Chen J, Anderson AH, Sondheimer JH, Lash JP, Townsend RR, Go AS, Feldman HI, Shah SJ, Wolf M, Isakova T, Mehta RC |
2023 | |
Cardiomyopathy in chronic kidney disease: clinical features, biomarkers and the contribution of murine models in understanding pathophysiology
Junho CV, Frisch J, Soppert J, Wollenhaupt J, Noels H |
Clinical Kidney Journal | 2023 |
Associations between anemia and FGF23 in the CKiD study.
Thomas E, Klomhaus AM, Laster ML, Furth SL, Warady BA, Salusky IB, Hanudel MR |
Pediatric nephrology (Berlin, Germany) | 2023 |
High pretransplant FGF23 level is associated with persistent vitamin D insufficiency and poor graft survival in kidney transplant patients
Ryu JH, Jeon HJ, Han R, Jung HY, Kim MG, Huh KH, Park JB, Kang KP, Han S, Yang J |
Scientific Reports | 2023 |
Fibroblast growth factor 23 but not copeptin is independently associated with kidney failure and mortality in patients with chronic kidney disease
Michon-Colin A, Metzger M, Bankir L, Gauci C, Brunel M, Baron S, Prot-Bertoye C, Stengel B, Thervet E, Haymann JP, Boffa JJ, Vrtovsnik F, Flamant M, Houillier P, Prie D, Courbebaisse M |
Clinical Kidney Journal | 2023 |
Novel mechanism of the COVID-19 associated coagulopathy (CAC) and vascular thromboembolism.
Singh M, Pushpakumar S, Zheng Y, Smolenkova I, Akinterinwa OE, Luulay B, Tyagi SC |
2023 | |
Echocardiographic manifestations in end-stage renal disease.
Ito T, Akamatsu K |
Heart Failure Reviews | 2023 |
Cardioprotective and Antifibrotic Effects of Low-Dose Renin-Angiotensin-Aldosterone System Inhibitors in Type 1 Diabetic Rat Model.
Balogh DB, Molnar A, Degi A, Toth A, Lenart L, Saeed A, Barczi A, Szabo AJ, Wagner LJ, Reusz G, Fekete A |
International journal of molecular sciences | 2023 |
The Efficacy, Safety, and Economic Outcomes of Using Ferric Derisomaltose for the Management of Iron Deficiency in China: A Rapid Health Technology Assessment
Yun L, YuMei Z, BN V, Tang Q, Feng C |
Cureus | 2023 |
NT-proBNP Mediates the Association Between FGF23 and All-Cause Mortality in Individuals With Type 2 Diabetes.
van der Vaart A, Bakker SJL, Laverman GD, van Dijk PR, de Borst MH |
Journal of the American Heart Association | 2023 |
'Phos'tering a Clear Message: The Evolution of Dietary Phosphorus Management in Chronic Kidney Disease.
Biruete A, Hill Gallant KM, Lloyd L, Meade A, Moe SM, St-Jules DE, Kistler BM |
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation | 2023 |
The Dietary Fiber Inulin Slows Progression of Chronic Kidney Disease–Mineral Bone Disorder (CKD‐MBD) in a Rat Model of CKD
Biruete A, Chen NX, Metzger CE, Srinivasan S, O'Neill K, Fallen PB, Fonseca A, Wilson HE, de Loor H, Evenepoel P, Swanson KS, Allen MR, Moe SM |
JBMR Plus | 2023 |
Exploring the implications of blocking renin-angiotensin-aldosterone system and fibroblast growth factor 23 in early left ventricular hypertrophy without chronic kidney disease
Watanabe K, Fujii H, Okamoto K, Kono K, Goto S, Nishi S |
Frontiers in Endocrinology | 2023 |
Phosphate and Coronary Artery Disease in Patients with Chronic Kidney Disease.
Ogata H, Sugawara H, Yamamoto M, Ito H |
Journal of Atherosclerosis and Thrombosis | 2023 |
Fibroblast Growth Factor (FGF) 23 and FGF Receptor 4 promote cardiac metabolic remodeling in chronic kidney disease
Fuchs MA, Burke EJ, Latic N, Murray S, Li H, Sparks M, Abraham D, Zhang H, Rosenberg P, Hänzelmann S, Hausmann F, Huber T, Erben R, Fisher-Wellman K, Bursac N, Wolf M, Grabner A |
Research square | 2023 |
Beta Blockade Prevents Cardiac Morphological and Molecular Remodelling in Experimental Uremia.
Chinnappa S, Maqbool A, Viswambharan H, Mooney A, Denby L, Drinkhill M |
International journal of molecular sciences | 2023 |
Chronic Kidney Disease Associated with Ischemic Heart Disease: To What Extent Do Biomarkers Help?
Cepoi MR, Duca ST, Chetran A, Costache AD, Spiridon MR, Afrăsânie I, Leancă SA, Dmour BA, Matei IT, Miftode RS, Miftode L, Prepeliuc CS, Haba MȘ, Bădescu MC, Costache II |
Life Sciences | 2023 |
Fibroblast growth factor 23 independently predicts adverse outcomes after an acute coronary syndrome
Kallmeyer A, Pello A, Cánovas E, Aceña Á, González\u2010Casaus ML, Tarín N, Cristóbal C, Gutiérrez\u2010Landaluce C, Huelmos A, Rodríguez\u2010Valer A, González\u2010Lorenzo Ó, Alonso J, López\u2010Bescós L, Egido J, Mahillo I, Lorenzo Ó, Tuñón J |
ESC Heart Failure | 2023 |
The basics of phosphate metabolism
Wagner CA |
Nephrology Dialysis Transplantation | 2023 |
Iron Status and Cause-Specific Mortality After Kidney Transplantation
Vinke JS, Kremer D, Knobbe TJ, Grote Beverborg N, Berger SP, Bakker SJ, de Borst MH, Eisenga MF |
2023 | |
Impact of Electrocardiographic Parameters on Sudden Death in Patients Receiving Maintenance Hemodialysis: Ten-Year Outcomes of the Q-Cohort Study
Hiyamuta H, Yamada S, Nakano T, Taniguchi M, Masutani K, Tsuruya K, Kitazono T |
Journal of Atherosclerosis and Thrombosis | 2023 |
FGF-23, Left Ventricular Hypertrophy, and Mortality in Patients With CKD: A Revisit With Mediation Analysis
Hidaka N, Inoue K, Kato H, Hoshino Y, Koga M, Kinoshita Y, Takashi Y, Makita N, Fukumoto S, Nangaku M, Ito N |
2023 | |
Management of Cardiovascular Diseases in Chronic Hemodialysis Patients
Zhang Z, Wang Y |
2023 |