Phosphate control in reducing FGF23 levels in hemodialysis patients

Abstract

Background: In hemodialysis patients, high levels of Fibroblast Growth Factor 23 (FGF23) predict mortality. Our study was designed to test whether the control of serum phosphate is associated with a reduction in serum FGF23 levels. Additionally other variables with a potential effect on FGF23 levels were evaluated.

Material and methods: The effect of sustained (40-weeks) control of serum phosphate on FGF23 levels (intact and c-terminal) was evaluated in 21 stable hemodialysis patients that were not receiving calcimimetics or active vitamin D. Patients received non-calcium phosphate binders to maintain serum phosphate below 4.5 mg/dl. In an additional analysis, values of intact-FGF23 (iFGF23) and c-terminal FGF23 (cFGF23) from 150 hemodialysis patients were correlated with parameters of mineral metabolism and inflammation. Linear mixed models and linear regression were performed to evaluate longitudinal trajectories of variables and the association between FGF23 and the other variables examined.

Results: During the 40-week treatment, 12 of 21 patients achieved the target of serum phosphate <4.5 mg/dl. In these 12 patients, iFGF23 decreased to less than half whereas cFGF23 did not reduce significantly. In patients with serum phosphate >4.5 mg, iFGF23 and cFGF23 increased two and four-fold respectively as compared with baseline. Furthermore, changes in serum phosphate correlated with changes in C-reactive protein (hs-CRP). In our 150 hemodialysis patients, those in the higher tertile of serum phosphate also showed increased hs-CRP, iPTH, iFGF23 and cFGF23. Multiple regression analysis revealed that iFGF23 levels directly correlated with both serum phosphate and calcium, whereas cFGF23 correlated with serum phosphate and hs-CRP but not with calcium.

Conclusions: The control of serum phosphate reduced iFGF23. This reduction was also associated with a decreased in inflammatory parameters. Considering the entire cohort of hemodialysis patients, iFGF23 levels correlated directly with serum phosphate levels and also correlated inversely with serum calcium concentration. The levels of cFGF23 were closely related to serum phosphate and parameters of inflammation.

Fig 1. Serum concentrations of FGF23 at baseline and at week 40 in patients that achieved a serum phosphate concentration of <4.5 mg/dL and >4.5 mg/dL).

(A) Change in iFGF23 concentration; (B) change in serum cFGF23 concentration. Bars represent median and interquartile range. Serum iFGF23 decreased from 581.0 pg/mL (491.2–886.0) to 238.5 pg/mL (116.7–443.5) [median percent change of 63.8% (-75.2–5.40) in patients that achieved the target of phosphate <4.5 mg/dL. In patients with serum phosphate >4.5 mg/dL, iFGF23 increased from 709.0 pg/mL (179.0–1247.5) to 1445.0 pg/mL (884.0–1500), [median percent change of 65.3% (9.1–368.1). cFGF23 did not decreased in those patients that achieved the target [median percent change -36.3 (-60.1–48.3). However, in patients with a final serum phosphate >4.5 mg/dl, it increased from 864.5 RU/mL (262.7–1299) to 3402.0 RU/ml (1899.0–8875), [median percent change of 206.9% (108.9–1056.3)]. * P <0.05 vs baseline. ^# P <0.05 versus same time different group. ^## P<0.001versus same time, different group.

Fig 2. Change in parameters of mineral metabolism throughout the 40 weeks of follow-up in patients that completed the study with serum phosphate concentration above or below 4.5 mg/dL.

In the group of patients with a final serum P<4.5 mg/dL, 54, 80, 80, 80, 100 and 100% of them had a ranged serum phosphate below the target at week 0, 8, 16, 24, 32 and 40 respectively. On the contrary, in the group with a final serum phosphate >4.5 mg/dl, 66, 77, 44, 44, 33 and 0% of the patients had serum phosphate levels below the study target along the study period. Dots represent median and whiskers represent IQR. * Between-group differences P<0.05. ⁺ Within-group differences P<0.05 for different groups. ^# P<0.001 for global comparison of curves.

Fig 3. Scatter plot of serum phosphate levels and ln-CRP in the 150 patients on regular hemodialysis.

Fig 4

The degree of influence (expressed in percent) of the various independent variables on the serum levels of iFGF23 (A) and cFGF23 (B). The proportional contribution (Relative weights; RWs) of each of the independent variables on the serum levels of FGF23 were calculated. Statistical significance of RWs were assessed as described elsewhere [38,39]. Statistical significance is based on the values of confidence intervals; if zero is excluded from the confidence interval, the RW is significant. The RWs significance test was run only for variables that showed statistical significance in the linear regression models. The proportional contribution of serum iPTH, 25 (OH) D, 1,25 (OH) ₂ D, ferritin, calcium dialysate, the use of cinacalcet or paricalcitol, calcium-based, and calcium-free phosphate binders are grouped as “others” since their individual contribution was limited. S4 Table shows the detailed proportionate contribution of each variable for the entire population and separated according to phosphate levels below or above the median. Lowercase letters above columns identify different groups analyzed, a1-b1 overall population, a2-b2 patients with P<4.35 mg/dL and a3-b3 patients with P>4.35 mg/dL for iFGF23 and cFGF23 respectively. For iFGF23 (A) RWs of serum phosphate (CI for significance 0.24–0.47), ionized calcium [iCa] (CI for significance 0.001–0.07) and hs-CRP (CI for significance 0.01–0.10) were significantly different in the entire population (a₁₎. Moreover, RWs of serum phosphate was significantly greater than the RWs of iCa, hs-CRP and age RWs`. In patients with P<4.35 mg/dL (a₂₎, RWs of serum iCa (CI for significance 0.01–0.26) and phosphate (CI for significance 0.14–0.41) were significant as compared to the other variables. Interestingly, there was no difference between the RWs of phosphate and iCa in this group of patients (a₂). In patients with phosphate above the median (P>4.35 mg/dL) [a₃], only the RWs of hs-CRP (CI for significance 0.00–0.12) and phosphate (CI for significance 0.06–0.45) were significant. The RW of phosphate (59.9%) was significantly greater than that of the RWs of age (CI for significance -0.45—-0.04), hs-CRP (CI for significance -0.44—-0.02), and iCa (CI for significance -0.49—-0.07). (B) Regarding cFGF23, in the overall population (b₁) serum phosphate remained to be the main contributor (40.6%). Together with phosphate (CI for significance 0.18–0.34), RWs of hs-CRP (CI for significance 0.10–0.26), dialysis vintage (CI for significance 0.01–0.14), and age (CI for significance 0.008–0.12) were also significant. RWs of phosphate and hs-CRP were not different (CI for significance -0.20–0.04). Contribution of hs-CRP was far more important than that of iCa (31.0 vs 1.0%); (b₁). In the group of patients with P<4.35 mg/dL (b₂), hs-CRP (CI for significance 0.09–0.40) and phosphate (CI for significance 0.02–0.20) were the two significant RWs. hs-CRP contributed far more than phosphate, age and dialysis vintage. Finally, in the group of patients with P>4.35 mg/dL (b₃), dialysis vintage (CI for significance 0.05–0.32), hs-CRP (CI for significance 0.01–0.17), and serum phosphate (CI for significance 0.03–0.31) were the significant RWs. There were no differences between RWs of these three variables.