Single Measurements of Carboxy-Terminal Fibroblast Growth Factor 23 and Clinical Risk Prediction of Adverse Outcomes in CKD

Am J Kidney Dis. 2019 Dec;74(6):771-781. doi: 10.1053/j.ajkd.2019.05.026. Epub 2019 Aug 21.

Abstract

Rationale & objective: An elevated fibroblast growth factor 23 (FGF-23) level is independently associated with adverse outcomes in populations with chronic kidney disease, but it is unknown whether FGF-23 testing can improve clinical risk prediction in individuals.

Study design: Prospective cohort study.

Setting & participants: Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study (n = 3,789).

Exposure: Baseline carboxy-terminal FGF-23 (cFGF-23) level.

Outcomes: All-cause and cardiovascular (CV) mortality, incident end-stage renal disease (ESRD), heart failure (HF) admission, and atherosclerotic events at 3, 5, and 8 years.

Analytical approach: We assessed changes in model performance by change in area under the receiver operating characteristic curve (ΔAUC), integrated discrimination improvement (IDI), relative IDI, and net reclassification index (NRI) above standard clinical factors. We performed sensitivity analyses, including an additional model comparing the addition of phosphate rather than cFGF-23 level and repeating our analyses using an internal cross-validation cohort.

Results: Addition of a single baseline value of cFGF-23 to a base prediction model improved prediction of all-cause mortality (ΔAUC, 0.017 [95% CI, 0.001-0.033]; IDI, 0.021 [95% CI, 0.006-0.036]; relative IDI, 32.7% [95% CI, 8.5%-56.9%]), and HF admission (ΔAUC, 0.008 [95% CI, 0.0004-0.016]; IDI, 0.019 [95% CI, 0.004-0.034]; relative IDI, 10.0% [95% CI, 1.8%-18.3%]), but not CV mortality, ESRD, or atherosclerotic events at 3 years of follow-up. The NRI did not reach statistical significance for any of the 3-year outcomes. The incremental predictive utility of cFGF-23 level diminished in analyses of the 5- and 8-year outcomes. The cFGF-23 models outperformed the phosphate model for each outcome.

Limitations: Power to detect increased CV mortality likely limited by low event rate. The NRI is not generalizable without accepted prespecified risk thresholds.

Conclusions: Among individuals with CKD, single measurements of cFGF-23 improve prediction of risks for all-cause mortality and HF admission but not CV mortality, ESRD, or atherosclerotic events. Future studies should evaluate the predictive utility of repeated cFGF-23 testing.

Keywords: Fibroblast growth factor 23 (FGF23); atherosclerotic disease; biomarker; cardiovascular mortality; chronic kidney disease (CKD); clinical risk prediction; end-stage renal disease (ESRD); heart failure (HF); mortality.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Area Under Curve
  • Biomarkers / blood
  • Cause of Death*
  • Cohort Studies
  • Disease-Free Survival
  • Female
  • Fibroblast Growth Factors / blood*
  • Humans
  • Kaplan-Meier Estimate
  • Kidney Failure, Chronic / blood*
  • Kidney Failure, Chronic / mortality*
  • Kidney Failure, Chronic / therapy
  • Male
  • Middle Aged
  • Predictive Value of Tests
  • Prospective Studies
  • ROC Curve
  • Renal Insufficiency, Chronic / blood*
  • Renal Insufficiency, Chronic / mortality*
  • Renal Insufficiency, Chronic / therapy
  • Risk Assessment
  • Survival Analysis
  • United States

Substances

  • Biomarkers
  • Fibroblast Growth Factors
  • fibroblast growth factor 23