Fibroblast Growth Factor 23 Associates with Death in Critically Ill Patients

Abstract

Background and objectives: Dysregulated mineral metabolism is a common and potentially maladaptive feature of critical illness, especially in patients with AKI, but its association with death has not been comprehensively investigated. We sought to determine whether elevated plasma levels of the osteocyte-derived, vitamin D-regulating hormone, fibroblast growth factor 23 (FGF23), are prospectively associated with death in critically ill patients with AKI requiring RRT, and in a general cohort of critically ill patients with and without AKI.

Design, setting, participants, & measurements: We measured plasma FGF23 and other mineral metabolite levels in two cohorts of critically ill patients (n=1527). We included 817 patients with AKI requiring RRT who enrolled in the ARF Trial Network (ATN) study, and 710 patients with and without AKI who enrolled in the Validating Acute Lung Injury biomarkers for Diagnosis (VALID) study. We hypothesized that higher FGF23 levels at enrollment are independently associated with higher 60-day mortality.

Results: In the ATN study, patients in the highest compared with lowest quartiles of C-terminal (cFGF23) and intact FGF23 (iFGF23) had 3.84 (95% confidence interval, 2.31 to 6.41) and 2.08 (95% confidence interval, 1.03 to 4.21) fold higher odds of death, respectively, after adjustment for demographics, comorbidities, and severity of illness. In contrast, plasma/serum levels of parathyroid hormone, vitamin D metabolites, calcium, and phosphate were not associated with 60-day mortality. In the VALID study, patients in the highest compared with lowest quartiles of cFGF23 and iFGF23 had 3.52 (95% confidence interval, 1.96 to 6.33) and 1.93 (95% confidence interval, 1.12 to 3.33) fold higher adjusted odds of death.

Conclusions: Higher FGF23 levels are independently associated with greater mortality in critically ill patients.

Keywords: Acute Kidney Injury; Acute Lung Injury; Biomarkers; Calcium, Dietary; Cohort Studies; Comorbidity; Confidence Intervals; Critical Illness; Demography; Fibroblast Growth Factors; Humans; Minerals; Osteocytes; Phosphates; Renal Replacement Therapy; Vitamin D; acute renal failure; fibroblast growth factor 23; parathyroid hormone; renal dialysis.

Graphical abstract

Figure 1.

Associations between FGF23 and other mineral metabolites in the ARF Trial Network study. Restricted cubic spline graphs depict the relationships between cFGF23, iFGF23, and (A and B) 25D, (C and D) 1,25D, and (E and F) 24,25D₃ (n=394 for each graph). Four knots were specified at the fifth, 35th, 65th, and 95th FGF23 percentiles. The 95% confidence intervals are indicated by the shaded areas. (G) The Spearman correlation coefficient for each comparison. *P<0.05; **P<0.01; ***P<0.001. 25D, 25-hydroxyvitamin D; 1,25D, 1,25-dihydroxyvitamin D; 24,25D₃, 24,25-dihydroxyvitamin D₃; cFGF23, C-terminal fibroblast growth factor 23; iFGF23, intact fibroblast growth factor 23; Ln, natural log-transformed; PO₄, phosphate; PTH, parathyroid hormone; r_s, Spearman coefficient; RU/ml, reference units per milliliter.

Figure 2.

Higher cFGF23 and iFGF23 levels associate with increased 60-day mortality in the ARF Trial Network study. (A) Odds ratios for 60-day mortality according to quartiles of cFGF23 and iFGF23 levels. Quartile 1 was the reference (R) group in all models. cFGF23 levels by quartile: quartile 1, <1072 RU/ml; quartile 2, 1078–3587 RU/ml; quartile 3, 3608–12,951 RU/ml; quartile 4, >12,983 RU/ml. iFGF23 levels by quartile: quartile 1, <30 pg/ml; quartile 2, 30–88 pg/ml; quartile 3, 88–240 pg/ml; quartile 4, >241 pg/ml. (B) Odds ratios for 60-day mortality according to natural log–transformed mineral metabolite levels standardized to 1 SD. Model 1 is unadjusted. Model 2 is adjusted for demographics and comorbidities (age, sex, race, baseline eGFR, diabetes, cancer, congestive heart failure, and chronic liver disease). Model 3 is further adjusted for severity of illness (intensive care unit type, mechanical ventilation, Acute Physiology and Chronic Health Evaluation II score, RRT before randomization, treatment group, type of RRT, oliguria, sepsis, hypotension, white blood cell count, hemoglobin, and serum/plasma levels of albumin, creatinine, and IL-6). 25D, 25-hydroxyvitamin D; 1,25D, 1,25-dihydroxyvitamin D; 24,25D₃, 24,25-dihydroxyvitamin D₃; cFGF23, C-terminal fibroblast growth factor 23; iFGF23, intact fibroblast growth factor 23; PTH, parathyroid hormone; RU/ml, reference units per milliliter.

Figure 3.

Higher cFGF23 and iFGF23 levels associate with higher 60-day mortality in the Validating Acute Lung Injury biomarkers for Diagnosis (VALID) study. (A) Odds ratios for 60-day mortality according to quartiles of cFGF23 and iFGF23 levels. Quartile 1 was the reference (R) group in all models. cFGF23 levels by quartile: quartile 1, <211 RU/ml; quartile 2, 212–595 RU/ml; quartile 3, 602–1868 RU/ml; quartile 4, >1886 RU/ml. iFGF23 levels by quartile: quartile 1, <24 pg/ml; quartile 2, 24–44 pg/ml; quartile 3, 44–87 pg/ml; quartile 4, >87 pg/ml. (B) Odds ratios for 60-day mortality according to natural log–transformed FGF23 levels standardized to 1 SD. Model 1 is unadjusted. Model 2 is adjusted for demographics and comorbidities (age, sex, race, baseline eGFR, diabetes, cancer, congestive heart failure, and chronic liver disease). Model 3 is further adjusted for severity of illness (intensive care unit type, mechanical ventilation, Acute Physiology and Chronic Health Evaluation II score, sepsis, hypotension, white blood cell count, hemoglobin, serum creatinine, and AKI presence and severity on enrollment). cFGF23, C-terminal fibroblast growth factor 23; iFGF23, intact fibroblast growth factor 23; RU/ml, reference units per milliliter.

Figure 4.

Higher cFGF23 and iFGF23 quartiles associate with higher 1-year mortality in the Validating Acute Lung Injury biomarkers for Diagnosis (VALID) study. (A and B) Kaplan–Meier curves showing survival during the first year after enrollment, stratified according to quartiles of cFGF23 and iFGF23. (C) Hazard ratios for 1-year mortality according to cFGF23 and iFGF23 quartiles. Model 1 is unadjusted. Model 2 is adjusted for demographics and comorbidities (age, sex, race, baseline eGFR, diabetes, cancer, congestive heart failure, and chronic liver disease). Model 3 is further adjusted for severity of illness (intensive care unit type, mechanical ventilation, Acute Physiology and Chronic Health Evaluation II score, sepsis, hypotension, white blood cell count, hemoglobin, serum creatinine, and AKI presence and severity on enrollment). cFGF23, C-terminal fibroblast growth factor 23; iFGF23, intact fibroblast growth factor 23; Q, quartile; REF, reference group; RU/ml, reference units per milliliter.