title: Inflammation and elevated levels of fibroblast growth factor 23 are independent risk factors for death in chronic kidney disease.
abstract: Inflammation is a consequence of chronic kidney disease (CKD) and is associated with adverse outcomes in many clinical settings. Inflammation stimulates production of fibroblast growth factor 23 (FGF23), high levels of which are independently associated with mortality in CKD. Few large-scale prospective studies have examined inflammation and mortality in patients with CKD, and none tested the interrelationships among inflammation, FGF23, and risk of death. Therefore, we conducted a prospective investigation of 3875 participants in the Chronic Renal Insufficiency Cohort (CRIC) study with CKD stages 2 to 4 to test the associations of baseline plasma interleukin-6, high-sensitivity C-reactive protein, and FGF23 levels with all-cause mortality, censoring at the onset of end-stage renal disease. During a median follow-up of 6.9 years, 550 participants died (20.5/1000 person-years) prior to end-stage renal disease. In separate multivariable-adjusted analyses, higher levels of interleukin-6 (hazard ratio per one standard deviation increase of natural log-transformed levels) 1.35 (95% confidence interval, 1.25-1.46), C-reactive protein 1.28 (1.16-1.40), and FGF23 1.45 (1.32-1.60) were each independently associated with increased risk of death. With further adjustment for FGF23, the risks of death associated with interleukin-6 and C-reactive protein were minimally attenuated. Compared to participants in the lowest quartiles of inflammation and FGF23, the multivariable-adjusted hazard ratio of death among those in the highest quartiles of both biomarkers was 4.38 (2.65-7.23) for interleukin-6 and FGF23, and 5.54 (3.04-10.09) for C-reactive protein and FGF23. Thus, elevated levels of interleukin-6, C-reactive protein, and FGF23 are independent risk factors for mortality in CKD.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Jair
authors.initials: J
authors.lastname: Munoz Mendoza
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Isakova
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Cai
authors.affiliation: Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Liz Y
authors.initials: LY
authors.lastname: Bayes
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Faul
authors.affiliation: Department of Medicine, Duke University School of Medicine, Durham, NC, USA; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Julia J
authors.initials: JJ
authors.lastname: Scialla
authors.affiliation: Section of Nephrology, Department of Medicine, University of Illinois, Chicago, IL, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Lash
authors.affiliation: Section of Nephrology and Hypertension, Department of Medicine, Tulane School of Medicine, New Orleans, LA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Section of Nephrology and Hypertension, Department of Medicine, Tulane School of Medicine, New Orleans, LA, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: He
authors.affiliation: Selzman Institute for Kidney Health, Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Section of Nephrology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA.
authors.forename: Sankar
authors.initials: S
authors.lastname: Navaneethan
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Negrea
authors.affiliation: Joslin Diabetes Center, Beth Israel Deaconess Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Sylvia E
authors.initials: SE
authors.lastname: Rosas
authors.affiliation: Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.affiliation: University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Nessel
authors.affiliation: University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Dawei
authors.initials: D
authors.lastname: Xie
authors.affiliation: University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Amanda Hyre
authors.initials: AH
authors.lastname: Anderson
authors.affiliation: Division of Renal Diseases and Hypertension, George Washington University, Washington, DC, USA.
authors.forename: Dominic S
authors.initials: DS
authors.lastname: Raj
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. Electronic address: myles.wolf@duke.edu.
authors.forename: Myles
authors.initials: M
authors.lastname: Wolf
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood*; D002097:C-Reactive Protein / Q000032:analysis; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood*; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000175:diagnosis / Q000401:mortality*; D018836:Inflammation Mediators / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic / Q000097:blood / Q000175:diagnosis / Q000401:mortality; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000175:diagnosis / Q000401:mortality*; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D014481:United States; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D015415:Biomarkers; C000717427:FGF23 protein, human; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D002097:C-Reactive Protein
keywords: CKD; FGF23; inflammation; mortality