title: Induction of cardiac FGF23/FGFR4 expression is associated with left ventricular hypertrophy in patients with chronic kidney disease.
abstract: In chronic kidney disease (CKD), serum concentrations of fibroblast growth factor 23 (FGF23) increase progressively as glomerular filtration rate declines, while renal expression of the FGF23 coreceptor Klotho decreases. Elevated circulating FGF23 levels are strongly associated with mortality and with left ventricular hypertrophy (LVH), which is a major cause of cardiovascular death in CKD patients. The cardiac FGF23/FGF receptor (FGFR) system and its role in the development of LVH in humans have not been addressed previously.
  
  
  
  We conducted a retrospective case-control study in 24 deceased patients with childhood-onset end-stage renal disease (dialysis: n = 17; transplanted: n = 7), and 24 age- and sex-matched control subjects. Myocardial autopsy samples of the left ventricle were evaluated for expression of endogenous FGF23, FGFR isoforms, Klotho, calcineurin and nuclear factor of activated T-cells (NFAT) by immunohistochemistry, immunofluorescence microscopy, qRT-PCR and western blotting.
  
  
  
  The majority of patients presented with LVH (67%). Human cardiomyocytes express full-length FGF23, and cardiac FGF23 is excessively high in patients with CKD. Enhanced myocardial expression of FGF23 in concert with Klotho deficiency strongly correlates with the presence of LVH. Cardiac FGF23 levels associate with time-averaged serum phosphate levels, up-regulation of FGFR4 and activation of the calcineurin-NFAT signaling pathway, an established mediator of cardiac remodelling and LVH. These changes are detected in patients on dialysis but not in those with a functioning kidney transplant.
  
  
  
  Our results indicate a strong association between LVH and enhanced expression levels of FGF23, FGFR4 and calcineurin, activation of NFAT and reduced levels of soluble Klotho in the myocardium of patients with CKD. These alterations are not observed in kidney transplant patients.
authors.affiliation: Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Leifheit-Nestler
authors.affiliation: Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Große Siemer
authors.affiliation: Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Flasbart
authors.affiliation: Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Richter
authors.affiliation: Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Kirchhoff
authors.affiliation: Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Ziegler
authors.affiliation: Institute for Forensic Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Klintschar
authors.affiliation: Institute of Pathology, University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
authors.forename: Jan U
authors.initials: JU
authors.lastname: Becker
authors.affiliation: Institute of Pathology, University Hospital Rostock, Strempelstr. 14, 18055 Rostock, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Erbersdobler
authors.affiliation: Division of Pediatric Nephrology, University Children's Hospital Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Aufricht
authors.affiliation: Division of Pediatric Nephrology, University Children's Hospital Motol, V Uvalu 84, 15006, Prague, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Seeman
authors.affiliation: Department of Pediatrics, University Hospital Rostock, Ernst-Heydemann-Str. 8, 18057 Rostock, Germany.
authors.forename: Dagmar-Christiane
authors.initials: DC
authors.lastname: Fischer
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, 1580 NW 10th Avenue (R-762), Miami, FL 33136, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Faul
authors.affiliation: Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Haffner
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D016022:Case-Control Studies; D002648:Child; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D012189:Retrospective Studies
chemical_list: D015415:Biomarkers; C000717427:FGF23 protein, human; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4
keywords: Klotho; chronic kidney disease; fibroblast growth factor 23; fibroblast growth factor receptor 4; left ventricular hypertrophy