Fibroblast growth factor 23 and Inflammation in CKD

Abstract

Background and objectives: Levels of fibroblast growth factor 23 (FGF23) and inflammatory markers are commonly elevated in CKD, and each is associated with adverse clinical outcomes. This study tested the hypothesis that FGF23 is independently associated with inflammation in CKD.

Design, setting, participants, & measurements: The association between levels of FGF23 and the inflammatory markers IL-6, C-reactive protein (CRP), TNF-α, and fibrinogen was assessed in a cross-sectional analysis of 3879 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study between June 2003 and September 2008.

Results: FGF23 correlated directly with IL-6 (r=0.4), CRP (r=0.2), TNF-α (r=0.4), and fibrinogen (r=0.3; P<0.001 for each). In univariate and multivariable-adjusted linear regression analyses, natural log (ln) transformed FGF23 was significantly associated with lnIL-6, lnCRP, lnTNF-α, and fibrinogen (P<0.001 for each). Each unit higher lnFGF23 was associated with severe inflammation, defined as levels of all inflammatory markers in the highest 25th percentile, in univariate (odds ratio [OR], 2.4 [95% confidence interval (CI), 2.0-2.9]) and multivariable-adjusted (OR, 2.0 [95% CI, 1.6-2.5]) logistic regression analyses. Ascending FGF23 quartiles were independently associated with severe inflammation (OR, 5.6 for the highest versus lowest FGF23 quartile [95% CI, 2.3-13.9]; P for trend < 0.001).

Conclusions: Higher FGF23 levels are independently associated with higher levels of inflammatory markers in patients with CKD and with significantly greater odds of severe inflammation. Future studies should evaluate whether inflammation modifies the association between FGF23 and adverse outcomes in CKD.

Figure 1.

Median inflammatory marker levels across fibroblast growth factor 23 (FGF23) quartiles and body mass index (BMI) categories. (A) C-reactive protein (CRP). (B) IL-6. Q1, FGF23 quartile 1 (<95.8 RU/ml); Q2, FGF23 quartile 2 (95.8 to <145.4 RU/ml); Q3, FGF23 quartile 3 (≥145.5 to <239.1 RU/ml); Q4, FGF23 quartile 4 (≥ 239.2 RU/ml).

Figure 2.

Crude and multivariable-adjusted logistic regression analyses evaluating the association between fibroblast growth factor 23 (FGF23) with severe inflammation. Severe inflammation was defined as being in the highest 25th percentile of each of the IL-6, C-reactive protein, TNF-α, and fibrinogen (n=135) distributions. Error bars indicate 95% confidence intervals. ^aAdjusted for age, sex, black race, Hispanic ethnicity, diabetes, current smoking, body mass index (BMI), use of statins, estimated GFR, and urinary albumin-to-creatinine ratio. ^bAdjusted for values in model A plus further adjustment for phosphate and parathyroid hormone. P for trend < 0.001 for all three models. Q1, FGF23 quartile 1 (<95.8 RU/ml); Q2, FGF23 quartile 2 (95.8–145.4 RU/ml); Q3, FGF23 quartile 3 (145.5–239.1 RU/ml); Q4, FGF23 quartile 4 (≥239.20 RU/ml).