Serum bone markers in ROD patients across the spectrum of decreases in GFR: Activin A increases before all other markers

Abstract

Introduction: Renal osteodystrophy (ROD) develops early in chronic kidney disease (CKD) and progresses with loss of kidney function. While intact parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3 (1,25D), and fibroblast growth factor-23 (FGF-23) levels are usually considered the primary abnormalities in ROD development, the role of serum activin A elevations in CKD and its relationships to ROD have not been explored. The aims of this study were to evaluate serum activin A at different CKD stages, and to establish the relationships between activin A, bone biomarkers, and bone histomorphometric parameters.

Materials and methods: 104 patients with CKD stages 2 - 5D underwent bone biopsies. We measured in the serum activin A, BSAP, DKK1, FGF-23, α-Klotho, intact PTH, sclerostin, TRAP-5b, and 1,25D. Biochemical results were compared across CKD stages and with 19 age-matched controls with normal kidney function.

Results: Median activin A levels were increased in all stages of CKD compared to controls from 544 pg/mL in CKD 2 (431 - 628) to 1,135 pg/mL in CKD 5D (816 - 1,456), compared to 369 pg/mL in controls (316 - 453, p < 0.01). The increase of activin A in CKD 2 (p = 0.016) occurred before changes in the other measured biomarkers. Activin A correlated with intact PTH and FGF-23 (r = 0.65 and 0.61; p < 0.01) and with histomorphometric parameters of bone turnover (BFR/BS, Acf, ObS/BS and OcS/BS; r = 0.47 - 0.52; p < 0.01). These correlations were comparable to those found with intact PTH and FGF-23.

Conclusion: Serum activin A levels increase starting at CKD 2 before elevations in intact PTH and FGF-23. Activin A correlates with bone turnover similar to intact PTH and FGF-23. These findings suggest a role for activin A in early development of ROD.

Figure 1.. Relationships between serum levels of activin A and levels of eGFR. Results of patients with CKD 5D (n = 34) are given by mean ± 95% confidence intervals. Dashed line represents linear regression (R² = 0.316, p < 0.01).

Figure 2.. Serum levels of activin A in patients with CKD stages 2 – 5D. Results sharing the same letters are not significantly different.

Figure 3.. Serum levels of sclerostin, intact PTH, FGF-23, and 1,25D in patients with CKD stages 2 – 5D. Results sharing the same letters are not significantly different.

Figure 4.. Levels of serum activin A in low, normal, and high bone turnover patients with CKD from stage 2 to 5D (group means + 95% confidence intervals). Results sharing the same letters are not significantly different.

Figure 5.. Levels of serum biochemical parameters in patients (CKD from stage 2 to 5D) with low, normal, and high bone turnover (group means + 95% confidence intervals). Results sharing the same letters are not significantly different.