Update on fibroblast growth factor 23 in chronic kidney disease

Abstract

Chronic kidney disease (CKD) is a public health epidemic that affects millions of people worldwide. Presence of CKD predisposes individuals to high risks of end-stage renal disease (ESRD), cardiovascular disease, and premature death. Disordered phosphate homeostasis with elevated circulating levels of fibroblast growth factor 23 (FGF23) is an early and pervasive complication of CKD. CKD is likely the most common cause of chronically elevated FGF23 levels, and the clinical condition in which levels are most markedly elevated. Although increases in FGF23 levels help maintain serum phosphate in the normal range in CKD, prospective studies in populations of pre-dialysis CKD, incident and prevalent ESRD, and kidney transplant recipients demonstrate that elevated FGF23 levels are independently associated with progression of CKD and development of cardiovascular events and mortality. It was originally thought that these observations were driven by elevated FGF23 levels acting as a highly sensitive biomarker of toxicity due to phosphate. However, FGF23 itself has now been shown to mediate 'off-target,' direct, end-organ toxicity in the heart, which suggests that elevated FGF23 levels may be a novel mechanism of adverse outcomes in CKD. This report reviews recent advances in FGF23 biology relevant to CKD, the classical effects of FGF23 on mineral homeostasis, and the studies that established FGF23 excess as a biomarker and novel mechanism of cardiovascular disease. The report concludes with a critical review of the effects of different therapeutic strategies targeting FGF23 reduction and how these might be leveraged in a future randomized trial aimed at improving outcomes in CKD.

Figure 1. Representative levels of FGF23 in health, various states of CKD (orange bars), and in primary hypophosphatemic disorders (blue bars)

The dual y-axis presents FGF23 levels on the scales of the two commercially available assay platforms. The intact assay detects biologically intact FGF23 exclusively (iFGF23), whereas the C-terminus (cFGF23) assay is capable of detecting both the intact molecule and its C-terminal fragments. The grey area represents the presumed but incompletely defined normal ranges. “1° hypoP, FGF23” refers to hypophosphatemic disorders caused by primary FGF23 excess, for example, X-linked hypophosphatemia. “1° hypoP, non-FGF23” refers to hypophosphatemic disorders caused by mechanisms other than FGF23 excess, for example, hereditary hypophosphatemic rickets with hypercalciuria, in which FGF23 levels are secondarily suppressed.^, CKD, chronic kidney disease; ESRD, end-stage renal disease; Tx, transplantation

Figure 2. FGF23 is an independent risk factor for mortality in CKD stages 2–4

The cumulative incidence of death of CKD stage 2–4 patients increases significantly with ascending quartiles of baseline FGF23 levels in unadjusted analyses (plot) and after full multivariable adjustment (hazard ratios and 95% confidence intervals in the inset).

Figure 3. Hypothesis to reconcile the seemingly paradoxical effects of FGF23 and vitamin D on survival in CKD

Baseline and change in FGF23 levels are plotted against time among 6 hypothetical patient groups. The spectrum of risk of mortality associated with FGF23 is demonstrated by the red background gradient (higher risk is darker red). Dashed lines represent active vitamin D treated-groups, and solid lines represent untreated groups. “X” connotes death. The known effect of elevated baseline FGF23 on risk of mortality is represented by the higher baseline FGF23 and earlier mortality among groups 1–3 vs. 4–6. The main effect of active vitamin D therapy on survival is represented by the longer survival of groups 1 and 5 vs. 2 and 6. In all groups, FGF23 levels increase with longer duration of ESRD, but the rate of increase is greater among those treated with active vitamin D (greater slopes of FGF23 in groups 1 and 4 vs. 2; 3 and 5 vs. 6). The hypothesized interaction between active vitamin D treatment and FGF23 is represented by the significantly greater slopes of increase in FGF23 among active vitamin D-treated groups who die sooner compared with those who survive longer (crossing lines of groups 4 vs. 3). Thus, it is hypothesized that survival is longest in group 5, which had low baseline FGF23, received active vitamin D therapy, but experienced only a modest increase in FGF23 in response.