A low fractional excretion of Phosphate/Fgf23 ratio is associated with severe abdominal Aortic calcification in stage 3 and 4 kidney disease patients

Abstract

Background: Vascular calcification (VC) contributes to high mortality rates in chronic kidney disease (CKD). High serum phosphate and FGF23 levels and impaired phosphaturic response to FGF23 may affect VC. Therefore, their relative contribution to abdominal aortic calcification (AAC) was examined in patients CKD stages 3-4.

Methods: Potential risk factors for AAC, measured by the Kauppila Index (KI), were studied in 178 patients.

Results: In multivariate linear analysis, AAC associated positively with age, male gender, CKD-stage, presence of carotid plaques (CP) and also with FGF23, but negatively with fractional excretion of phosphate (FEP). Intriguingly, FEP increased with similar slopes with elevations in PTH, with reductions in GFR, and also with elevations in FGF23 but the latter only in patients with none (KI = 0) or mild (KI = 1-5) AAC. Lack of a FEP-FGF23 correlation in patients with severe AAC (KI > 5) suggested a role for an impaired phosphaturic response to FGF23 but not to PTH in AAC. Logistic and zero-inflated analysis confirmed the independent association of age, CKD stage, male gender and CP with AAC, and also identified a threshold FEP/FGF23 ratio of 1/3.9, below which the chances for a patient of presenting severe AAC increased by 3-fold. Accordingly, KI remained unchanged as FEP/FGF23 ratios decreased from 1/1 to 1/3.9 but markedly increased in parallel with further reductions in FEP/FGF23 < 1/3.9.

Conclusions: In CKD 3-4, an impaired phosphaturic response to FGF23 with FEP/FGF23 < 1/3.9 associates with severe AAC independently of age, gender or CP.

Figure 1

Resistance to FGF23-driven phosphaturia in CKD patients with severe abdominal aortic calcification. Linear regression models for the relationship between FEP and serum FGF23 (A), or serum PTH (B) or estimated GFR (C) in the three subgroups of CKD patients defined by their Kauppila Index (KI; Black: KI = 0, no calcification; Green: KI = 1 to 5, moderate calcification; Red: KI > 5, severe calcification) in the whole patient population (Left side panels) or in patients with estimated GFR under 30 ml/min (Right side panels).

Figure 2

Biphasic relationship between the severity of abdominal aortic calcification with the phosphaturic response to FGF23. Linear regression (Gray line) and non parametric regression (Black, continuous lines) depicting the relationships between the ratio of FEP/FGF23 (in logarithmic scale (base 2): log₂(FEP/FGF23)), in the X axis, with the Kauppila Index (Y axis). The softer continuous lanes mark the dispersion from the mean fit (see Methods for specifics). The box plot below the X axis shows that the cut-off point FEP/FGF23 = 1/3.9 coincides with the median for the log₂(FEP/FGF23) in our patient population. Note that the cut-off point FEP/FGF23 = 1/3.9 also marks an inflexion point for quite distinct average changes for KI with changes in FEP/FGF23 ratios above and below the cut-off: No change in KI for FEP/FGF23 ratios above the cut off; Parallel increases in KI with decreases in FEP/FGF23 ratios below the cut-off. Note in the X axis, the FEP/FGF23 ratios corresponding to the values of log₂(FEP/FGF23). The Box plot for KI distribution in our patients is depicted to the left of the Y axes.

Figure 3

Validation of the logistic model identifying factors independently associated with severe abdominal aortic calcification. ROC curve depicting the high sensitivity of the logistic regression analysis of factors independently associated with severe abdominal aortic calcification (KI < 5) vs. no calcification (KI = 0) including all patients. The ROC curve includes male gender, age, CKD stage, the presence of carotid plaques, and the log₂ (FEP/FGF23). The ratio FEP/FGF23 was introduced as a binary variable with a cutoff point of 1/3.9.

Figure 4

The severity of AAC is higher in patients with a FEP/FGF23 below the threshold FEP/FGF23 = 1/3.9. Box-plot analysis of the AAC measured by the Kauppila index (KI) in patients with a ratio FEP/FGF23 below 1/3.9 or equal or above 1/3.9. Patients were divided in two groups defined by the median of the ratio (1/3.9).