Bishop Charles W, Ashfaq Akhtar, Choe John, Strugnell Stephen A, Johnson Laura L, Norris Keith C, Sprague Stuart M
OPKO Health, Miami, Florida, USA.
Next Generation Clinical Research, Fitchburg, Wisconsin, USA.
Am J Nephrol. 2025 Jun 4:1-11. doi: 10.1159/000546615.
Serum concentrations of 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D) decline as chronic kidney disease (CKD) advances, becoming insufficient without effective vitamin D repletion and driving onset of secondary hyperparathyroidism (SHPT). Randomized controlled trials (RCTs) in non-dialysis CKD patients have established that extended-release calcifediol (ERC) effectively raises 25D and 1,25D and reduces elevated intact parathyroid hormone (iPTH) despite the progressive loss of renal cytochrome P450 25D-1α-hydroxylase (CYP27B1), suggesting its potential usefulness in treating SHPT in end-stage kidney disease (ESKD).
This pilot RCT explored the safety and efficacy of oral ERC to raise serum total 25D to ≥50 ng/mL, normalize circulating 1,25D, and reduce elevated iPTH in ESKD patients requiring regular hemodialysis (HD). Forty-four adults from 13 US clinics requiring HD three times per week were washed out from iPTH-lowering therapies and randomized 3:1 to 26 weeks of treatment with ERC (300 µg/HD) or placebo. Participants had a mean age of 56.4 ± 11.6 years, body mass index of 32.7 ± 8.1 kg/m2, 46% were female, 68% black, 30% white, and 24% Hispanic. At randomization, iPTH had to be 300 to <1,200 pg/mL, 25D <50 ng/mL, corrected serum calcium <9.8 mg/dL, and phosphorus <6.5 mg/dL. These parameters were monitored weekly or biweekly and 1,25D quarterly.
Mean (±SE) serum total 25D rose with ERC treatment from 24.1 ± 1.7 ng/mL at baseline (BL) to steady-state levels of 157.7 ± 10.4 (p < 0.001) after 12 weeks, with all individual levels exceeding 50 ng/mL but varying inversely with body weight. Serum 25D levels declined with placebo treatment from 36.0 ± 5.3 to 30.6 ± 5.5 ng/mL. Mean 1,25D rose from 9.4 ± 1.2 to 50.7 ± 7.8 pg/mL (p < 0.001) with ERC and concentrations surpassed 19.9 pg/mL (lower limit of normal) in 93% of participants. Mean iPTH increased 19.8 ± 10.6% from BL with placebo (497.6 ± 69.2 to 593.1 ± 95.1 pg/mL) but decreased 1.7 ± 4.7% (p < 0.05) with ERC (530.4 ± 29.4 to 529.6 ± 43.7 pg/mL). A strong correlation was observed with ERC treatment between serum 1,25D and 25D (R2 = 0.8248; p < 0.001) indicating that, on average, 1,25D normalized as 25D reached ≥50 ng/mL. Increases in mean serum calcium or phosphorus, episodes of hypercalcemia, or treatment-emergent adverse events were not observed with ERC treatment.
ERC safely raised serum total 25D, normalized low serum 1,25D, and stabilized elevated plasma iPTH in this pilot placebo-controlled RCT involving ESKD patients requiring regular HD. The observed increases in 1,25D indicated that ERC restored adequate endogenous vitamin D hormone production via substrate-driven conversion to calcitriol in extrarenal tissues expressing CYP27B1, thereby preventing further SHPT progression.
随着慢性肾脏病（CKD）进展，血清25-羟维生素D（25D）和1,25-二羟维生素D（1,25D）浓度下降，若未进行有效的维生素D补充则会变得不足，并促使继发性甲状旁腺功能亢进（SHPT）的发生。针对非透析CKD患者的随机对照试验（RCT）已证实，尽管肾细胞色素P450 25D-1α-羟化酶（CYP27B1）功能逐渐丧失，但缓释骨化二醇（ERC）可有效提高25D和1,25D水平，并降低升高的全段甲状旁腺激素（iPTH），这表明其在终末期肾病（ESKD）患者SHPT治疗中具有潜在应用价值。
本项先导性RCT探讨了口服ERC在需要定期血液透析（HD）的ESKD患者中，将血清总25D水平提高至≥50 ng/mL、使循环1,25D水平正常化以及降低升高的iPTH的安全性和有效性。来自美国13家诊所的44名每周需要进行3次HD的成年人停用了降低iPTH的疗法，并按3:1随机分组，接受为期26周的ERC（300 µg/HD）或安慰剂治疗。参与者的平均年龄为56.4±11.6岁，体重指数为32.7±8.1 kg/m²，46%为女性，68%为黑人，30%为白人，24%为西班牙裔。随机分组时，iPTH必须在300至<1200 pg/mL之间，25D<50 ng/mL，校正血清钙<9.8 mg/dL，磷<6.5 mg/dL。每周或每两周监测这些参数，每季度监测1,25D。
接受ERC治疗后，血清总25D的平均（±标准误）水平从基线（BL）时 的24.1±1.7 ng/mL升至12周后的稳态水平157.7±10.4（p<0.001），所有个体水平均超过50 ng/mL，但与体重呈负相关。接受安慰剂治疗后，血清25D水平从36.0±5.3降至30.6±5.5 ng/mL。接受ERC治疗后，平均1,25D从9.4±1.2升至50.7±7.8 pg/mL（p<0.001），93%的参与者浓度超过19.9 pg/mL（正常下限）。接受安慰剂治疗后，平均iPTH从BL时升高了19.8±10.6%（从497.6±69.2升至593.1±95.1 pg/mL），而接受ERC治疗后则降低了1.7±4.7%（p<0.05）（从530.4±29.4降至529.6±43.7 pg/mL）。在ERC治疗中观察到血清1,25D与25D之间存在强相关性（R² = 0.8248；p<0.001），表明平均而言，当25D达到≥50 ng/mL时1,25D恢复正常。接受ERC治疗未观察到平均血清钙或磷升高、高钙血症发作或治疗中出现的不良事件。
在这项涉及需要定期HD的ESKD患者的先导性安慰剂对照RCT中，ERC安全地提高了血清总25D水平，使低水平的血清1,25D正常化，并稳定了升高的血浆iPTH。观察到的1,25D升高表明，ERC通过在表达CYP27B1的肾外组织中经底物驱动转化为骨化三醇，恢复了内源性维生素D激素的充分产生，从而防止SHPT进一步进展。
