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.

引言：在患有继发性甲状旁腺功能亢进（SHPT）的非透析慢性肾脏病（ND-CKD）患者中，使用ERC使完整甲状旁腺激素（iPTH）持续降低30%与估算肾小球滤过率（eGFR）下降减缓相关。这种iPTH降低通常需要将血清总25-羟基维生素D（25D）升高至≥50 ng/mL，但ERC的剂量上限（60 μg/天）可能限制这一目标的实现，因此引出了辅助性（adj）活性维生素D（AVD）是否适合进一步降低iPTH的问题。

方法：本随机对照试验（RCT）纳入78例接受ERC治疗38周的ND-CKD成人患者，旨在探讨辅助性AVD是否能安全增强ERC带来的iPTH降低效果，并进一步减缓eGFR下降速率。参与者平均年龄66岁，体重指数35 kg/m²，41%为女性，63%为白人，36%为黑人，19%为西班牙裔。开始ERC治疗时，参与者血浆iPTH为85-<500 pg/mL，eGFR为15-<60 mL/min/1.73 m²，血清25D为10-<30 ng/mL，校正血清钙（Ca）为8.4-<9.8 mg/dL，血清磷（P）为2.0-<5.0 mg/dL，且无大量白蛋白尿（>300 mg/g肌酐）。基线时（BL；第38周），参与者血浆iPTH>70 pg/mL且血清Ca<9.8 mg/dL，按3:1:1:1比例随机分为两组：一组（n=40）在额外14周的每日ERC（60 μg）治疗基础上加用辅助性每日口服骨化三醇（0.25 μg）、度骨化醇（0.5 μg）或帕立骨化醇（1.0 μg）；另一组（n=38）仅接受ERC治疗。在基线和治疗结束（EOT）期间测量eGFR、iPTH、25D、Ca、P及成纤维细胞生长因子23（FGF23）。

结果：基线时各组间无显著差异。两组基线平均25D为65 ng/mL，至治疗结束时均升高14 ng/mL（p<0.001）。基线平均iPTH为137 pg/mL，辅助性AVD治疗组进一步降低35.4%（p<0.001），而单纯ERC组仅降低2.2%。辅助性AVD治疗组的平均Ca、P和FGF23分别升高0.40 mg/dL（p<0.001）、0.27 mg/dL（p<0.01）和49.1 pg/mL（155%；p<0.001），而单纯ERC组无变化。基线平均eGFR为25.4 mL/min/1.73m²，辅助性AVD治疗组下降11.8%（p<0.05），单纯ERC组下降3.0%。

结论：在此剂量下，辅助性AVD使长期接受ERC治疗的轻至中度SHPT的ND-CKD患者iPTH多降低35%，但血清Ca和P平均分别升高0.40和0.27 mg/dL，FGF23升高超过2倍，eGFR下降加快4倍，提示ERC联合AVD的不良效应超过了单纯ERC治疗中iPTH降低带来的肾脏保护作用。需要更大规模、更长时间的RCT来验证这一结果。