B- CRF: rheumatological and mineral complications
B- CRF: metabolic and endocrine complications
C- 05: hyperphosphatemia
F- 08: metabolic complications
Fibroblast Growth Factor 23 and Risks of Mortality and End-Stage Renal
Disease in Patients With Chronic Kidney Disease
Tamara Isakova, MD, MMSc; Huiliang Xie, PhD; Wei Yang, PhD; Dawei Xie, PhD; Amanda Hyre
Anderson, PhD, MPH; Julia Scialla, MD, MHS; Patricia Wahl, PhD; Orlando M. Gutiérrez, MD,
MMSc; Susan Steigerwalt, MD; Jiang He, MD, PhD; Stanley Schwartz, MD; Joan Lo, MD; Akinlolu
Ojo, MD, PhD, MPH; James Sondheimer, MD; Chi-yuan Hsu, MD, MSc; James Lash, MD; Mary
Leonard, MD, MSCE; John W. Kusek, PhD; Harold I. Feldman, MD, MSCE; Myles Wolf, MD,
MMSc; for the Chronic Renal Insufficiency Cohort (CRIC) Study Group
Journal : JAMA
Year : 2011 / Month : June
Volume : 305
Pages : 2432-2439
ABSTRACT
Context
A high level of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-23) is
associated with mortality in patients with end-stage renal disease, but little is known about its
relationship with adverse outcomes in the much larger population of patients with earlier stages of
chronic kidney disease.
Objective
To evaluate FGF-23 as a risk factor for adverse outcomes in patients with chronic kidney disease.
Design, Setting, and Participants
A prospective study of 3879 participants with chronic kidney disease stages 2 through 4 who
enrolled in the Chronic Renal Insufficiency Cohort between June 2003 and September 2008.
Main Outcome Measures
All-cause mortality and end-stage renal disease.
Results
At study enrollment, the mean (SD) estimated glomerular filtration rate (GFR) was 42.8 (13.5)
mL/min/1.73 m2, and the median FGF-23 level was 145.5 RU/mL (interquartile range [IQR], 96-239
reference unit [RU]/mL). During a median follow-up of 3.5 years (IQR, 2.5-4.4 years), 266
participants died (20.3/1000 person-years) and 410 reached end-stage renal disease (33.0/1000
person-years). In adjusted analyses, higher levels of FGF-23 were independently associated with a
greater risk of death (hazard ratio [HR], per SD of natural log-transformed FGF-23, 1.5; 95%
confidence interval [CI], 1.3-1.7). Mortality risk increased by quartile of FGF-23: the HR was 1.3
(95% CI, 0.8-2.2) for the second quartile, 2.0 (95% CI, 1.2-3.3) for the third quartile, and 3.0 (95%
CI, 1.8-5.1) for the fourth quartile. Elevated fibroblast growth factor 23 was independently
associated with significantly higher risk of end-stage renal disease among participants with an
estimated GFR between 30 and 44 mL/min/1.73 m2 (HR, 1.3 per SD of FGF-23 natural logtransformed FGF-23; 95% CI, 1.04-1.6) and 45 mL/min/1.73 m2 or higher (HR, 1.7; 95% CI, 1.12.4), but not less than 30 mL/min/1.73 m2.
Conclusion
Elevated FGF-23 is an independent risk factor for end-stage renal disease in patients with
relatively preserved kidney function and for mortality across the spectrum of chronic kidney
disease.
COMMENTS
Fibroblast growth factor 23 (FGF-23) is an endocrine hormone that regulates phosphorus
metabolism. Circulating levels of FGF-23 increase progressively as kidney function declines. It
increases in chronic kidney disease as an appropriate physiological adaptation to maintain neutral
phosphate balance and normal serum phosphate levels in the setting of reduced renal capacity for
phosphate excretion.
Preventing increases in serum phosphate is likely beneficial in chronic
reports of greater risk of adverse renal and cardiovascular outcomes in
hyperphosphatemia. Small studies suggest that an elevated FGF-23 level
factor for mortality among patients undergoing dialysis, and for more rapid
in earlier stages of chronic kidney disease.
kidney disease given
association with overt
is an independent risk
loss of kidney function
Whether FGF-23 is associated with greater risks of mortality and end-stage renal disease in the
much larger population of patients with earlier stages of chronic kidney disease is unknown and
was tested in this study, a prospective cohort study of individuals with chronic kidney disease
stages 2 through 4.
FGF-23 was measured in baseline samples from 3879 of the 3939 participants after a single thaw.
The mean (SD) estimated GFR at the baseline visit was 42.8 mL/min/1.73 m2 (13.5 mL/min/1.73
m2). Although the mean (SD) serum phosphate level was 3.7 mg/dL (0.7 mg/dL), and 89% of
participants had normal phosphate levels (<4.6 mg/dL), the median FGF-23 level was 145.5
RU/mL (interquartile range [IQR], 96-239 RU/mL), which is more than 3-fold higher than the
median of 43 RU/mL (IQR, 29-72 RU/mL) in a population with a low prevalence of chronic kidney
disease. Fibroblast growth factor 23 correlated with estimated GFR (r = −0.52; P < .001), cystatin
C (r = 0.59; P < .001), serum phosphate (r = 0.35; P < .001), parathyroid hormone (r = 0.37;
P < .001), FePi (r = 0.26; P < .001), and hemoglobin (r = −0.36; P < .001). After FGF-23,
parathyroid hormone was the next closest correlate of estimated GFR (r = −0.47; P < .001).
During a median follow-up of 3.5 years, 266 participants died (20.3/1000 person-years) and 410
reached end-stage renal disease (33.0/1000 person-years). Median FGF-23 levels were
significantly higher in those who died (234; IQR, 142-419 RU/mL) or reached end-stage renal
disease (236; IQR, 160-372 RU/mL) than in those who remained event-free (133; IQR, 91-210
RU/mL; P < .001 for each).
Participants in the highest vs the lowest quartile demonstrated a 4.3-fold greater risk of death, and
the intermediate quartiles demonstrated intermediate risks. Further adjustment for traditional
cardiovascular risk factors; use of cardioprotective and renoprotective medications; and serum
calcium, phosphate, and parathyroid hormone levels minimally attenuated the relationship between
FGF-23 and risk of death
An elevated level of FGF-23 is an independent risk factor for mortality in a referred population of
patients with chronic kidney disease stages 2 through 4. The effect was minimally confounded by
other factors known to influence survival and was specific to FGF-23 among the mineral
metabolites. The mechanisms that underlie the association between elevated levels of FGF-23 and
mortality are unclear. FGF-23 could be a risk factor by itself.
Pr. Jacques CHANARD
Professor of Nephrology