Ashfaq Akhtar, Choe John, Tabash Samir, Strugnell Stephen A, Johnson Laura L, Bishop Charles W
OPKO Health, Miami, FL, USA.
MHN Pharma Consulting, Whitby, ON, Canada.
BMC Nephrol. 2025 Aug 7;26(1):442. doi: 10.1186/s12882-025-04361-3.
Hemodialysis (HD) patients lose renal CYP27B1 (cytochrome P450 25-hydroxyvitamin D-1α-hydroxylase) as kidney function declines causing low serum total 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D), and elevated intact parathyroid hormone (iPTH). Most require vitamin D hormone treatment which increases the risk of hypercalcemia. A recent randomized controlled trial (RCT) in HD patients showed that extended-release calcifediol (ERC) could safely raise serum 25D to high levels (≥ 50 ng/mL) and drive sufficient alternative production of 1,25D by extra-renal CYP27B1, potentially avoiding the need for hormone treatment.
A 41-year-old Caucasian male requiring regular HD was overdosed with 900 (rather than 300) µg/HD of ERC for 10 weeks in the RCT referenced above. When the overdosing was recognized, serum 25D had increased 18-fold (from 19 to 339 ng/mL), 1,25D had risen 23-fold (from 6 to 137 pg/mL), and iPTH had decreased 67% (from 440 to 146 pg/mL) with no impact on calcium, phosphorus or treatment-emergent adverse events noted.
The observations from this case report are consistent with the conclusion from the full RCT with ERC in HD patients that serum 25D repletion can control elevated iPTH in advanced chronic kidney disease by supporting adequate extra-renal 1,25D production. They also indicate that serum 25D levels required for adequate extra-renal 1,25D production and effective iPTH control are much higher than commonly used repletion targets of 20 or 30 ng/mL, and published estimates of serum 25D toxicity thresholds are probably too low for ERC. These observations, however, require substantiation in further clinical trials with ERC in end-stage kidney disease patients.
随着肾功能下降，血液透析（HD）患者会丧失肾脏细胞色素P450 25-羟维生素D-1α-羟化酶（CYP27B1），导致血清总25-羟维生素D（25D）和1,25-二羟维生素D（1,25D）水平降低，而完整甲状旁腺激素（iPTH）水平升高。大多数患者需要接受维生素D激素治疗，这会增加高钙血症的风险。最近一项针对HD患者的随机对照试验（RCT）表明，缓释骨化二醇（ERC）可安全地将血清25D水平提高到较高水平（≥50 ng/mL），并通过肾外CYP27B1驱动1,25D的充分替代生成，从而可能避免激素治疗的必要性。
在上述RCT中，一名41岁需要定期进行血液透析的白人男性，过量服用了900（而非300）μg/次血液透析剂量的ERC，持续10周。当发现用药过量时，血清25D升高了18倍（从19 ng/mL升至339 ng/mL），1,25D升高了23倍（从6 pg/mL升至137 pg/mL），iPTH降低了67%（从440 pg/mL降至146 pg/mL），且未对钙、磷或治疗中出现的不良事件产生影响。
本病例报告的观察结果与HD患者使用ERC的完整RCT得出的结论一致，即血清25D补充可通过支持肾外1,25D的充分生成来控制晚期慢性肾病中升高的iPTH。这些结果还表明，肾外1,25D充分生成及有效控制iPTH所需血清25D水平远高于常用的20或30 ng/mL补充目标，而且已公布的血清25D毒性阈值对ERC来说可能过低。然而，这些观察结果需要在终末期肾病患者中使用ERC的进一步临床试验中得到证实。
