Junichi Ishigami1,2, Jonathan T Taliercio3, Harold I Feldman4, Anand Srivastava5, Raymond R Townsend4, Debbie L Cohen4, Edward J Horwitz6, Panduranga Rao7, Jeanne Charleston8, Jeffrey C Fink9, Ana C Ricardo10, James Sondheimer11, Teresa K Chen12, Myles Wolf13, Tamara Isakova5, Lawrence J Appel8,2, Kunihiro Matsushita8,2. 1. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland jishiga1@jhu.edu. 2. Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. 3. Department of Nephrology and Hypertension, Cleveland Clinic Foundation, Cleveland, Ohio. 4. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania. 5. Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 6. Division of Nephrology, MetroHealth Medical Center, Cleveland, Ohio. 7. Division of Nephrology, University of Michigan, Ann Arbor, Michigan. 8. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. 9. Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland. 10. Division of Nephrology, University of Illinois, Chicago, Illinois. 11. Division of Nephrology and Hypertension, Wayne State University School of Medicine, Detroit, Michigan. 12. Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland. 13. Division of Nephrology, Department of Medicine, and Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina.
Abstract
BACKGROUND: Risk of infectious disease is increased among individuals with CKD. Fibroblast growth factor 23 (FGF23) is often elevated in CKD, and may impair immune function directly or indirectly through proinflammatory and vitamin D-suppressing pathways. Whether FGF23 is associated with risk of infection has not been evaluated in a CKD population. METHODS: In 3655 participants of the Chronic Renal Insufficiency Cohort study, we evaluated the association of baseline plasma levels of C-terminal FGF23 with time to first hospitalization with major infection, defined by hospital discharge with a diagnosis code for urinary tract infection, pneumonia, cellulitis/osteomyelitis, or bacteremia/septicemia. Multivariable Cox models were used to estimate hazard ratios (HRs) and adjust for confounding. RESULTS: During a median follow-up of 6.5 years, 1051 individuals (29%) were hospitalized with major infection. Multivariable Cox analysis indicated a graded increase in the risk of infection with higher levels of FGF23 (HR, 1.51; 95% CI, 1.23 to 1.85 with the highest quartile [≥235.9 RU/ml] versus lowest quartile [<95.3 RU/ml]; HR, 1.26; 95% CI, 1.18 to 1.35 per SD increment in log FGF23). The association was consistent across infection subtypes and demographic and clinical subgroups, and remained significant after additional adjustment for biomarkers of inflammation (IL-6, TNF-α, high-sensitivity C-reactive protein, fibrinogen, and albumin), and bone mineral metabolism (25-hydroxyvitamin D, phosphorus, calcium, and parathyroid hormone). The association was consistent across infection subtypes of urinary tract infection (482 cases), cellulitis/osteomyelitis (422 cases), pneumonia (399 cases), and bacteremia/septicemia (280 cases). CONCLUSIONS: Among individuals with CKD, higher FGF23 levels were independently and monotonically associated with an increased risk of hospitalization with infection.
BACKGROUND: Risk of infectious disease is increased among individuals with CKD. Fibroblast growth factor 23 (FGF23) is often elevated in CKD, and may impair immune function directly or indirectly through proinflammatory and vitamin D-suppressing pathways. Whether FGF23 is associated with risk of infection has not been evaluated in a CKD population. METHODS: In 3655 participants of the Chronic Renal Insufficiency Cohort study, we evaluated the association of baseline plasma levels of C-terminal FGF23 with time to first hospitalization with major infection, defined by hospital discharge with a diagnosis code for urinary tract infection, pneumonia, cellulitis/osteomyelitis, or bacteremia/septicemia. Multivariable Cox models were used to estimate hazard ratios (HRs) and adjust for confounding. RESULTS: During a median follow-up of 6.5 years, 1051 individuals (29%) were hospitalized with major infection. Multivariable Cox analysis indicated a graded increase in the risk of infection with higher levels of FGF23 (HR, 1.51; 95% CI, 1.23 to 1.85 with the highest quartile [≥235.9 RU/ml] versus lowest quartile [<95.3 RU/ml]; HR, 1.26; 95% CI, 1.18 to 1.35 per SD increment in log FGF23). The association was consistent across infection subtypes and demographic and clinical subgroups, and remained significant after additional adjustment for biomarkers of inflammation (IL-6, TNF-α, high-sensitivity C-reactive protein, fibrinogen, and albumin), and bone mineral metabolism (25-hydroxyvitamin D, phosphorus, calcium, and parathyroid hormone). The association was consistent across infection subtypes of urinary tract infection (482 cases), cellulitis/osteomyelitis (422 cases), pneumonia (399 cases), and bacteremia/septicemia (280 cases). CONCLUSIONS: Among individuals with CKD, higher FGF23 levels were independently and monotonically associated with an increased risk of hospitalization with infection.
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