Adjunctive Active Vitamin D Decreases Kidney Function during Treatment of Secondary Hyperparathyroidism with Extended-Release Calcifediol in Non-Dialysis Chronic Kidney Disease in a Randomized Trial.

Introduction: Sustained 30% reductions of intact parathyroid hormone (iPTH) with extended-release calcifediol (ERC) are associated with slower decline in estimated glomerular filtration rate (eGFR) in non-dialysis chronic kidney disease (ND-CKD) patients with secondary hyperparathyroidism (SHPT). Such iPTH reductions usually require elevation of serum total 25-hydroxyvitamin D (25D) to ≥50 ng/mL, but achieving these reductions can be limited by the ERC dose ceiling (60 μg/day), raising the question of whether adjunctive active vitamin D (adj AVD) might be appropriate to further reduce iPTH.

Methods: This randomized controlled trial (RCT) examined whether adj AVD could safely increase iPTH reductions achieved with ERC and further reduce the rate of eGFR decline in 78 ND-CKD adults treated with ERC for 38 weeks. Participants had mean age of 66 years, body mass index of 35 kg/m2, were 41% female, 63% white, 36% black, 19% Hispanic. At ERC initiation, participants had plasma iPTH 85-<500 pg/mL, eGFR 15-<60 mL/min/1.73 m2, serum 25D 10-<30 ng/mL, corrected serum calcium (Ca) 8.4-<9.8 mg/dL, serum phosphorus (P) 2.0-<5.0 mg/dL, and absence of macroalbuminuria (>3 g/g creatinine). At baseline (BL; week 38), participants had plasma iPTH >70 pg/mL and serum Ca <9.8 mg/dL and were randomized 3:1:1:1 to daily ERC (60 μg) for 14 additional weeks with (n = 40) or without (n = 38) adj daily oral calcitriol (0.25 μg), doxercalciferol (0.5 μg), or paricalcitol (1.0 μg). Measurements of eGFR, iPTH, 25D, Ca, P, and fibroblast growth factor 23 (FGF23) were obtained at BL and through end of treatment (EOT).

Results: No significant intergroup differences were observed at BL. Mean 25D at BL was 65 ng/mL and rose 14 ng/mL by EOT in both groups (p < 0.001). Mean BL iPTH was 137 pg/mL and fell by a further 35.4% (p < 0.001) with adj AVD therapy versus 2.2% without. Mean Ca, P, and FGF23 increased with adj AVD by 0.40 mg/dL (p < 0.001), 0.27 mg/dL (p < 0.01), and 49.1 pg/mL (155%; p < 0.001), respectively, but remained unchanged with ERC alone. Mean BL eGFR was 25.4 mL/min/1.73 m2 and fell by 11.8% (p < 0.05) with adj AVD versus 3.0% without.

Conclusion: Adj AVD at these doses enabled 35% more iPTH reduction in ND-CKD patients with mild to moderate SHPT on long-term ERC treatment but increased mean serum Ca and P by 0.40 and 0.27 mg/dL, respectively, FGF23 by more than 2-fold, and eGFR decline by 4-fold, suggesting that adding AVD to ERC has untoward effects that override the nephrosparing impact of iPTH reductions with ERC treatment alone. Corroboration is warranted with a larger, longer RCT.