Inflammation and elevated levels of fibroblast growth factor 23 are independent risk factors for death in chronic kidney disease

Jair Munoz Mendoza, Tamara Isakova, Xuan Cai, Liz Y. Bayes, Christian H Faul, Julia J. Scialla, James P. Lash, Jing Chen, Jiang He, Sankar Navaneethan, Lavinia Negrea, Sylvia E. Rosas, Matthias Kretzler, Lisa Nessel, Dawei Xie, Amanda Hyre Anderson, Dominic S. Raj, Myles Wolf, Lawrence J. Appel, Harold I. FeldmanAlan S. Go, Jiang He, John W. Kusek, James P. Lash, Akinlolu Ojo, Raymond R. Townsend

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)711-719
Number of pages9
JournalKidney International
Volume91
Issue number3
DOIs
StatePublished - Mar 1 2017

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Chronic Renal Insufficiency
Inflammation
C-Reactive Protein
Interleukin-6
Mortality
Chronic Kidney Failure
fibroblast growth factor 23
Population Growth
Cohort Studies
Biomarkers
Prospective Studies
Confidence Intervals

Keywords

  • CKD
  • FGF23
  • inflammation
  • mortality

ASJC Scopus subject areas

  • Medicine(all)
  • Nephrology

Cite this

Inflammation and elevated levels of fibroblast growth factor 23 are independent risk factors for death in chronic kidney disease. / Munoz Mendoza, Jair; Isakova, Tamara; Cai, Xuan; Bayes, Liz Y.; Faul, Christian H; Scialla, Julia J.; Lash, James P.; Chen, Jing; He, Jiang; Navaneethan, Sankar; Negrea, Lavinia; Rosas, Sylvia E.; Kretzler, Matthias; Nessel, Lisa; Xie, Dawei; Anderson, Amanda Hyre; Raj, Dominic S.; Wolf, Myles; Appel, Lawrence J.; Feldman, Harold I.; Go, Alan S.; He, Jiang; Kusek, John W.; Lash, James P.; Ojo, Akinlolu; Townsend, Raymond R.

In: Kidney International, Vol. 91, No. 3, 01.03.2017, p. 711-719.

Research output: Contribution to journalArticle

Munoz Mendoza, J, Isakova, T, Cai, X, Bayes, LY, Faul, CH, Scialla, JJ, Lash, JP, Chen, J, He, J, Navaneethan, S, Negrea, L, Rosas, SE, Kretzler, M, Nessel, L, Xie, D, Anderson, AH, Raj, DS, Wolf, M, Appel, LJ, Feldman, HI, Go, AS, He, J, Kusek, JW, Lash, JP, Ojo, A & Townsend, RR 2017, 'Inflammation and elevated levels of fibroblast growth factor 23 are independent risk factors for death in chronic kidney disease', Kidney International, vol. 91, no. 3, pp. 711-719. https://doi.org/10.1016/j.kint.2016.10.021
Munoz Mendoza, Jair ; Isakova, Tamara ; Cai, Xuan ; Bayes, Liz Y. ; Faul, Christian H ; Scialla, Julia J. ; Lash, James P. ; Chen, Jing ; He, Jiang ; Navaneethan, Sankar ; Negrea, Lavinia ; Rosas, Sylvia E. ; Kretzler, Matthias ; Nessel, Lisa ; Xie, Dawei ; Anderson, Amanda Hyre ; Raj, Dominic S. ; Wolf, Myles ; Appel, Lawrence J. ; Feldman, Harold I. ; Go, Alan S. ; He, Jiang ; Kusek, John W. ; Lash, James P. ; Ojo, Akinlolu ; Townsend, Raymond R. / Inflammation and elevated levels of fibroblast growth factor 23 are independent risk factors for death in chronic kidney disease. In: Kidney International. 2017 ; Vol. 91, No. 3. pp. 711-719.
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AU - Munoz Mendoza, Jair

AU - Isakova, Tamara

AU - Cai, Xuan

AU - Bayes, Liz Y.

AU - Faul, Christian H

AU - Scialla, Julia J.

AU - Lash, James P.

AU - Chen, Jing

AU - He, Jiang

AU - Navaneethan, Sankar

AU - Negrea, Lavinia

AU - Rosas, Sylvia E.

AU - Kretzler, Matthias

AU - Nessel, Lisa

AU - Xie, Dawei

AU - Anderson, Amanda Hyre

AU - Raj, Dominic S.

AU - Wolf, Myles

AU - Appel, Lawrence J.

AU - Feldman, Harold I.

AU - Go, Alan S.

AU - He, Jiang

AU - Kusek, John W.

AU - Lash, James P.

AU - Ojo, Akinlolu

AU - Townsend, Raymond R.

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N2 - 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.

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