title: Associations of FGF-23 and sKlotho with cardiovascular outcomes among patients with CKD stages 2-4.
abstract: OBJECTIVE
  CKD-mineral and bone disorders (CKD-MBD) measures contribute to cardiovascular morbidity in patients with CKD. Among these, fibroblast growth factor (FGF)-23 and its coreceptor Klotho may exert direct effects on vascular and myocardial tissues. Klotho exists in a membrane-bound and a soluble form (sKlotho). Recent experimental evidence suggests sKlotho has vasculoprotective functions.
  
  
  METHODS
  Traditional and novel CKD-MBD variables were measured among 444 patients with CKD stages 2-4 recruited between September 2008 and November 2012 into the ongoing CARE FOR HOMe study. Across tertiles of baseline sKlotho and FGF-23, the incidence of two distinct combined end points was analyzed: (1) the first occurrence of an atherosclerotic event or death from any cause and (2) the time until hospital admission for decompensated heart failure or death from any cause.
  
  
  RESULTS
  Patients were followed for 2.6 (interquartile range, 1.4-3.6) years. sKlotho tertiles predicted neither atherosclerotic events/death (fully adjusted Cox regression analysis: hazard ratio [HR] for third versus first sKlotho tertile, 0.75 [95% confidence interval (95% CI), 0.43-1.30]; P=0.30) nor the occurrence of decompensated heart failure/death (HR for third versus first sKlotho tertile, 0.81 [95% CI, 0.39-1.66]; P=0.56). In contrast, patients in the highest FGF-23 tertile had higher risk for both end points in univariate analysis. Adjustment for kidney function attenuated the association between FGF-23 and atherosclerotic events/death (HR for third versus first FGF-23 tertile, 1.23 [95% CI, 0.58-2.61]; P=0.59), whereas the association between FGF-23 and decompensated heart failure/death remained significant after adjustment for confounders (HR for third versus first FGF-23 tertile, 4.51 [95% CI, 1.33-15.21]; P=0.02).
  
  
  CONCLUSIONS
  In this prospective observational study of limited sample size, sKlotho was not significantly related to cardiovascular outcomes. FGF-23 was significantly associated with future decompensated heart failure but not incident atherosclerotic events.
authors.affiliation: Department of Internal Medicine IV-Nephrology and Hypertension, Saarland University Medical Centre, Homburg, Germany;
authors.forename: Sarah
authors.initials: S
authors.lastname: Seiler
authors.affiliation: Department of Internal Medicine IV-Nephrology and Hypertension, Saarland University Medical Centre, Homburg, Germany;
authors.forename: Kyrill S
authors.initials: KS
authors.lastname: Rogacev
authors.affiliation: Labor Dr Limbach und Kollegen, Medizinisches Versorgungszentrum, Heidelberg, Germany; and.
authors.forename: Heinz J
authors.initials: HJ
authors.lastname: Roth
authors.affiliation: Department of Internal Medicine IV-Nephrology and Hypertension, Saarland University Medical Centre, Homburg, Germany;
authors.forename: Pagah
authors.initials: P
authors.lastname: Shafein
authors.affiliation: Department of Internal Medicine IV-Nephrology and Hypertension, Saarland University Medical Centre, Homburg, Germany;
authors.forename: Insa
authors.initials: I
authors.lastname: Emrich
authors.affiliation: Department of Internal Medicine IV-Nephrology and Hypertension, Saarland University Medical Centre, Homburg, Germany;
authors.forename: Stefan
authors.initials: S
authors.lastname: Neuhaus
authors.affiliation: Division of Nephrology and Immunology, RWTH University of Aachen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
authors.affiliation: Department of Internal Medicine IV-Nephrology and Hypertension, Saarland University Medical Centre, Homburg, Germany;
authors.forename: Danilo
authors.initials: D
authors.lastname: Fliser
authors.affiliation: Department of Internal Medicine IV-Nephrology and Hypertension, Saarland University Medical Centre, Homburg, Germany; gunnar.heine@uks.eu.
authors.forename: Gunnar H
authors.initials: GH
authors.lastname: Heine
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D050197:Atherosclerosis / Q000097:blood / Q000453:epidemiology; D002318:Cardiovascular Diseases / Q000097:blood* / Q000453:epidemiology*; D002423:Cause of Death; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood*; D005966:Glucuronidase / Q000097:blood*; D006333:Heart Failure / Q000097:blood / Q000453:epidemiology; D006760:Hospitalization; D006801:Humans; D015994:Incidence; D000090265:Klotho Proteins; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000453:epidemiology; D013997:Time Factors; D058017:Vascular Grafting
chemical_list: C000717427:FGF23 protein, human; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: arteriosclerosis; calcium; chronic renal disease; fibroblast