Fibroblast Growth Factor-23 and Risks of Cardiovascular and Noncardiovascular Diseases: A Meta-Analysis

Abstract

Fibroblast growth factor-23 (FGF-23) has been hypothesized to play a role in the increased risk of cardiovascular disease in patients with CKD. We identified prospective studies reporting associations between FGF-23 concentration and risk of cardiovascular events. Maximally adjusted risk ratios (RRs) were extracted for each outcome and scaled to a comparison of the top versus bottom third of the baseline FGF-23 concentration, and the results aggregated. Depending on the assay used, median FGF-23 concentrations were 43-74 RU/ml and 38-47 pg/ml in 17 general population cohorts; 102-392 RU/ml in nine cohorts of patients with CKD not requiring dialysis; and 79-4212 RU/ml and 2526-5555 pg/ml in eight cohorts of patients on dialysis. Overall, comparing participants in the top and bottom FGF-23 concentration thirds, the summary RRs (95% confidence intervals [95% CIs]) were 1.33 (1.12 to 1.58) for myocardial infarction, 1.26 (1.13 to 1.41) for stroke, 1.48 (1.29 to 1.69) for heart failure, 1.42 (1.27 to 1.60) for cardiovascular mortality, and 1.70 (1.52 to 1.91) for all-cause mortality. The summary RR for noncardiovascular mortality, calculated indirectly, was 1.52 (95% CI, 1.28 to 1.79). When studies were ordered by average differences in FGF-23 concentration between the top and bottom thirds, there was no trend in RRs across the studies. The similarly-sized associations between increased FGF-23 concentration and cardiovascular (atherosclerotic and nonatherosclerotic) and noncardiovascular outcomes, together with the absence of any exposure-response relationship, suggest that the relationship between FGF-23 and cardiovascular disease risk may be noncausal.

Meta-Analysis of the Association between Fibroblast Growth Factor 23 and Mortality and Cardiovascular Events in Hemodialysis Patients

“…In accordance with Marthi et al [29], our data support the conclusion that elevated FGF23 increases the risk of all-cause mortality and CVD. In a word, FGF23 is a potential risk prediction factor and may be help for clinical practice.…”

“…Marthi et al [29] confirmed the association between FGF23 and mortality by meta-analysis. But Marcais et al [23] provided that evaluating the FGF23 without Klotho data may over highlight the detrimental effect.…”

“…But recent studies put forward a doubt on the association between FGF23 and mortality [28,29]. Marthi et al [29] confirmed the association between FGF23 and mortality by meta-analysis.…”

Active Vitamin D in Chronic Kidney Disease: Getting Right Back Where We Started from?

“…Further, emerging data reveal that many stimuli outside of the mineral metabolism are able to increase FGF23 levels (inflammation, iron deficiency [63], high fat diet [64], as well as LV hypertrophy [65]). Lastly, a systematic review and meta-analysis of the prospective studies on the associations between FGF23 and the risk of different cardiovascular diseases suggests that the relationship between FGF23 and cardiovascular risk may be noncausal [66]. …”

The effect of frequent hemodialysis on matrix metalloproteinases, their tissue inhibitors, and FGF23: Implications for blood pressure and left ventricular mass modification in the Frequent Hemodialysis Network trials

“…Given that vascular smooth muscle cells in the presence of uremia and hyperphosphatemia are shown to transform into an osteoblastic phenotype, it is reasonable to hypothesize that reductions in phosphate and FGF23 coupled with enhanced clearance may in part contribute to the phenotypic changes in the arterial tree leading to a fall in systolic blood pressure . Whether FGF23 is a direct uremic cardiovascular toxin continues to be debated; in a recent meta‐analysis, some authors questioned the causal link between FGF23 and cardiovascular endpoints in chronic kidney disease . The present observation adds to the emerging evidence that FGF23 is modifiable by reduction in serum phosphorus .…”