This study investigated the association of four serum CKD–MBD biomarkers with aortic stiffness between PD patients with and without DM. The study's novel finding is that serum FGF23 independently predicted aortic PWV only in PD patients with DM, albeit with lower serum FGF23 levels.
The close relationship between FGF23 and aortic stiffness in CKD and ESRD is explained by several mechanisms. FGF23 accelerates phosphate-induced calcification of vascular smooth muscle cells by stimulating osteoblastic differentiation20, activates the renin-angiotensin-aldosterone system21, and directly impairs endothelial vasorelaxation22. Furthermore, FGF23 expression and serum levels are elevated in inflammatory states23,24. Several clinical observational studies have demonstrated associations between serum FGF23 levels and vascular stiffness at various stages of CKD. The large-scale Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study found that serum FGF23 was associated with arterial stiffness in community subjects with impaired renal function (estimated glomerular filtration rate less than 60 mL/min/1.73m2)25. The association between serum FGF23 and total body atherosclerosis was also confirmed in a PIVUS subsample26. In patients on hemodialysis, serum FGF23 was associated with aortic calcification27 and accelerated the progression of coronary arterial calcification28,29. In patients undergoing PD, elevated serum FGF23 levels have been linked to vascular calcification30 and carotid artery intima-media thickness31. However, studies comparing the potentially different impacts of FGF23 on aortic stiffness in patients with and without DM are scarce.
In our study, serum FGF23 levels were positively associated with aortic stiffness in PD patients with DM but not in those without. Consistent with our finding, a significant positive association between serum FGF23 levels and aortic stiffness was found in non-CKD patients with type 1 DM but not in those with no DM32. In patients with coronary artery disease, serum FGF-23 levels predicted adverse cardiovascular outcomes only in those with type 2 DM but not in those without33. This suggested that DM status may modify FGF23's effects on vascular pathology and clinical cardiovascular events. Although the underlying mechanisms remain unclear, some DM-specific vascular pathological factors, such as advanced glycosylated end products, insulin resistance, and reactive oxygen species, may interplay in the complex pathogenesis of CKD–MBD and act synergistically with FGF23 on changing vascular wall structure.
Several DM-related factors, such as advanced glycated end product and glycerol-3-phosphate accumulation and enhanced chronic inflammation, are known to stimulate FGF23 secretion16. In patients with CKD who did not undergo dialysis, those with DM have higher FGF23 levels17 and more rapidly rising serum levels34 than those without DM. Surprisingly, our PD patients with DM had significantly lower serum FGF23 levels. A similar finding had been reported in the Japan Dialysis Outcomes and Practice Patterns study (J-DOPPS) and the Hemodialysis (HEMO) cohort, two large prevalent hemodialysis cohorts in Japan and the United States, respectively35,36. This finding could be attributed in part to patient selection. In these ESRD populations, patients with DM tended to have a shorter dialysis vintage and more preserved residual renal function, two major determinants of serum FGF23 levels37,38. Furthermore, a recent study demonstrated that insulin suppressed FGF23 production by inhibiting the transcription factor forkhead box protein O139. Nevertheless, the positive correlation between relatively lower serum FGF23 levels and aortic PWV values in DM suggests that FGF23 is a more sensitive biomarker for aortic stiffness in PD patients with DM.
In our study, serum fetuin-A, a potent circulatory inhibitor of vascular calcification, was not associated with aortic stiffness in either the DM or nonDM groups. A similar finding was reported in two other dialysis cohorts40,41. As we all know, vascular calcification is a hallmark of CKD, but it is not the only factor contributing to aortic stiffness. Nevertheless, serum fetuin-A levels were found to be positively correlated with serum albumin levels in both PD patients with and without DM. High circulating fetuin-A levels reduced the inflammatory process, resulting in higher albumin levels42,43. Wang and colleagues found that lower serum fetuin-A levels in patients undergoing PD were associated with malnutrition, as assessed by serum albumin assay and subjective global assessment44.
Klotho is an antiaging protein, and its declining levels may be related to accelerated vascular aging. In the National Health and Nutrition Examination Survey (NHANES), a large cohort of the general population in the United States, serum klotho was found to be negatively associated with pulse pressure45. In contrast, in a general Chinese population, serum klotho levels did not predict BP or aortic PWV46. Similarly, in the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) cohort, serum klotho levels were not associated with brachial-to-ankle PWV in patients with advanced non-dialysis CKD47. In our patients undergoing PD, serum klotho was not associated with aortic PWV or pulse pressure. The discrepancy among these studies may be explained by differences in study populations and ethics.
The present study has several limitations that should be acknowledged. First, there was no image evaluation for aortic or coronary calcification, as well as other indices of vascular dysfunction, in this study. Second, neither vitamin D status nor inflammatory markers were assessed in this study. Third, the causal relationship between serum FGF23 and aortic stiffness cannot be established in this cross-sectional study, and longitudinal analyses are warranted to determine whether higher serum FGF23 levels contribute to accelerated aortic stiffness in patients with DM.
In conclusion, among CKD–MBD biomarkers, serum FGF23 was an independent predictor of aortic stiffness in PD patients with DM but not in those without DM. Further studies are needed to clarify the potential mechanisms underlying the effect of FGF23 and DM status interaction on aortic stiffness in patients undergoing PD.