Supplementary Material for: Adjunctive active vitamin D (AVD) decreases kidney function during treatment of secondary hyperparathyroidism (SHPT) with extended-release calcifediol (ERC) in non-dialysis chronic kidney disease (ND-CKD)

Introduction: Sustained 30% reductions of intact parathyroid hormone (iPTH) with ERC are associated with slower decline in estimated glomerular filtration rate (eGFR) in ND-CKD patients with 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 (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, 41% were 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 (>300 mg/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/1.73m2 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.