Elevated FGF23 is an independent risk factor for mortality in a referred population of patients with CKD stages 2 through 4. The effect was minimally confounded by other factors known to influence survival in CKD and was specific to FGF23 among the mineral metabolites we analyzed. These results are consistent with prior reports of greater risk of mortality in association with elevated FGF23 levels in patients undergoing hemodialysis,4, 5
kidney transplant recipients21
and patients with prior history of cardiovascular disease.20
Unexpectedly, FGF23 was more strongly associated with mortality than traditional cardiovascular and CKD-specific risk factors, most notably, reduced eGFR and proteinuria. These data emphasize the potential of FGF23 as a novel risk factor for mortality in CKD.
The mechanisms that underlie the association between elevated FGF23 and mortality are unclear. One possibility is that FGF23 is an excellent biomarker of toxicity of other factors in the family of disordered mineral metabolism, such as elevated serum phosphate and PTH. However, a recent meta-analysis demonstrated the poor relationship between PTH and mortality, and the modest effect of elevated serum phosphate.22
In the current study, similar to the few previous studies that performed direct comparisons,4, 5, 21
FGF23 was more strongly associated with mortality than other mineral metabolites, and its effect was neither confounded nor modified by phosphate or PTH. In addition, increased FePi, which is a measure of the physiological action of FGF23 on renal phosphate handling,19
was not associated with mortality. These findings suggest that mechanisms beyond mineral metabolism may underlie excess mortality in association with elevated FGF23.
Another possibility is that elevated FGF23 is a sensitive marker of the severity of kidney dysfunction that accurately conveys mortality risk associated with CKD but not directly attributable to FGF23. This also seems inadequate, however, given the previous report linking elevated FGF23 with mortality in a predominantly non-CKD cohort,20
and our observation of homogenous risk of mortality across the range of renal function regardless of whether it was quantified using the standard MDRD eGFR, iothalamate GFR or cystatin C. In addition, the specificity of the results for FGF23 relative to PTH, despite their similar correlation with eGFR, suggests that the effect of FGF23 on death may be acting through a mechanistic pathway that is at least partially independent of renal function. Finally, the observation that eGFR and proteinuria fell out as insignificant risk factors for mortality in multivariable models that included FGF23 suggests that rather than simply acting as a biomarker of CKD severity, elevated FGF23 may contribute to the excess mortality that was attributed to CKD in previous studies in which FGF23 levels were unavailable. Although postulating direct toxicity of FGF23 remains speculative,23
elevated FGF23 consistently associates with pathophysiologically plausible mechanisms of premature death including left ventricular hypertrophy, endothelial dysfunction, atherosclerosis and arterial calcification.24–28
Experimental or randomized human studies are needed to assign or refute a direct causal role for FGF23 in excess mortality.
The relationship between FGF23 and risk of ESRD was more complex. In the overall population, FGF23 associated with risk of ESRD until eGFR was added to the model. While this might suggest that elevated FGF23 is not a risk factor for ESRD, the relationship between FGF23 and ESRD was modified by eGFR, which was the most potent determinant of progression to ESRD. Unlike death, in which events were relatively balanced across the range of eGFR, analyses of ESRD in the overall population were driven primarily by participants with baseline eGFR < 30 ml/min/1.73m2. This group experienced the greatest number of ESRD events with incidence rates that were approximately 4-fold and 18-fold higher than those with eGFR of 30 – 45 and ≥ 45 ml/min/1.73m2, respectively (). When the analyses were stratified by kidney function, higher FGF23 emerged as an independent risk factor for ESRD in those with eGFR > 30 ml/min/1.73m2, and the effect size grew with higher eGFR. While these results suggest that FGF23 testing might help stratify risk of progression to ESRD in the growing number of patients found to have modestly reduced eGFR, confirmation by future studies is needed.
Limitations of the study include the lack of data on cause of death. Although greater risk of cardiovascular mortality is likely given previous reports of FGF23 and cardiovascular events,20
future studies should examine cause-specific mortality and risk of major cardiovascular events in CKD patients according to FGF23. Second, vitamin D levels were only available in subsets of participants. However, since adjustment for vitamin D levels or vitamin D treatment did not alter the point estimate for FGF23 similar to previous studies,4
it is unlikely that vitamin D confounds the relationship between FGF23 and mortality. Third, we did not study other biomarkers, such as troponin T and brain natriuretic peptide, which have been associated with adverse outcomes in CKD.13
Finally, the lack of a validated assay in CKD precluded us from measuring circulating levels of the soluble form of klotho, the FGF23 co-receptor that is expressed in the kidneys and parathyroid glands and that demonstrates anti-aging and vascular-protective effects.29, 30
Future studies should explore whether reduced expression of klotho due to CKD itself31
or secondary to increased FGF23 in CKD32
is a potential mediator of FGF23-associated mortality.
Previous reports of greater risk of mortality in association with elevated FGF23 levels among dialysis patients4, 5
established the possibility that FGF23 may be a novel predictor of adverse outcomes in patients with kidney disease. In the current study, we extend these results to the much larger population of patients with CKD stages 2 – 4 in whom treatment of disordered phosphorus metabolism is not recommended because their serum phosphate levels are usually normal. If the results of the current study are confirmed, and experimental studies support the hypothesis of direct toxicity of FGF23, future research should evaluate whether therapeutic or preventative strategies that lower FGF23 can improve outcomes.