Bishop Charles W, Ashfaq Akhtar, Strugnell Stephen A, Choe John, Patel Nilay, Norris Keith C, Sprague Stuart M
OPKO Health, Miami, Florida, USA.
David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
Am J Nephrol. 2024 Aug 27:1-10. doi: 10.1159/000541138.
Chronic kidney disease (CKD) drives onerous human and healthcare costs, underscoring an urgent need to avert disease progression. Secondary hyperparathyroidism (SHPT) develops as CKD advances, and persistently elevated parathyroid hormone (PTH) may be nephrotoxic and associated with earlier dialysis onset. This study examines, for the first time, the hypothesis that sustained reduction of elevated intact PTH (iPTH) with extended-release calcifediol (ERC) reduces the nephrotoxic impact of SHPT and forestalls renal decline.
Changes in estimated glomerular filtration rate (eGFR) were analyzed post hoc in 126 adults with SHPT, stage 3-4 CKD, and low serum 25-hydroxyvitamin D (25D) treated for 1 year with ERC in pivotal trials. ERC was administered at 30 μg/day increasing, as needed, to 60 μg/day to achieve ≥30% reductions in iPTH. Calcium, phosphorus, 25D, 1,25-dihydroxyvitamin D (1,25D), iPTH, eGFR, fibroblast growth factor-23 (FGF23), bone turnover markers (BTMs), and urine albumin-to-creatinine ratio (uACR) were measured at baseline and regular intervals. Participants were categorized by achievement (or not) of sustained ≥30% iPTH reductions over the last 2 quarters of treatment to evaluate differences in eGFR decline.
For all participants, 25D increased 58.5 ± 2.3 (SE) ng/mL (p < 0.001) by the end of treatment (EOT), 1,25D increased 10.1 ± 1.8 pg/mL (p < 0.001), iPTH decreased from 143.8 ± 5.8 pg/mL to 108.8 ± 7.2 (p < 0.001), BTMs improved (p < 0.01), and eGFR declined 2.2 ± 0.5 mL/min/1.73 m2 (p < 0.001). The rate of eGFR decline was >5-fold higher (p = 0.014) in participants who did not achieve sustained iPTH reductions of ≥30% (3.2 ± 0.7; 12.7 ± 2.2%) than in those who did (0.6 ± 0.8; 2.9 ± 2.4%). It was highest in the 30 participants who did not exhibit an iPTH lowering response in both of the last 2 quarters of treatment (5.4 ± 0.9; 20.9 ± 3.4%). Duration of iPTH reduction had no impact on safety parameters. Degree of iPTH reduction at EOT was also associated with slower CKD progression.
Sustained reduction of elevated iPTH with ERC treatment was associated with slower rates of eGFR decline in patients with SHPT and stage 3-4 CKD without raising safety concerns. A prospective trial is warranted to confirm this finding.
慢性肾脏病（CKD）带来了沉重的人力和医疗成本，凸显了避免疾病进展的迫切需求。随着CKD的进展会发生继发性甲状旁腺功能亢进（SHPT），而甲状旁腺激素（PTH）持续升高可能具有肾毒性，并与更早开始透析相关。本研究首次检验了以下假设：使用缓释骨化二醇（ERC）持续降低升高的全段甲状旁腺激素（iPTH）可降低SHPT的肾毒性影响并延缓肾功能衰退。
在关键试验中，对126例患有SHPT、3 - 4期CKD且血清25 - 羟维生素D（25D）水平低的成人进行了为期1年的ERC治疗，事后分析了估计肾小球滤过率（eGFR）的变化。ERC初始剂量为每日30μg，根据需要增加至每日60μg，以使iPTH降低≥30%。在基线和定期随访时测量钙、磷、25D、1,25 - 二羟维生素D（1,25D）、iPTH、eGFR、成纤维细胞生长因子23（FGF23）、骨转换标志物（BTMs）以及尿白蛋白与肌酐比值（uACR）。根据在治疗的最后两个季度是否实现iPTH持续降低≥30%对参与者进行分类，以评估eGFR下降的差异。
对于所有参与者，治疗结束时（EOT）25D升高58.5±2.3（标准误）ng/mL（p<0.001），1,25D升高10.1±1.8 pg/mL（p<0.001），iPTH从143.8±5.8 pg/mL降至108.8±7.2（p<0.001），BTMs改善（p<0.01），eGFR下降2.2±0.5 mL/min/1.73 m²（p<0.001）。未实现iPTH持续降低≥30%的参与者（3.2±0.7；12.7±2.2%）的eGFR下降速率比实现该目标的参与者（0.6±0.8；2.9±2.4%）高5倍以上（p = 0.014）。在治疗的最后两个季度均未出现iPTH降低反应的30名参与者中下降速率最高（5.4±0.9；20.9±3.4%）。iPTH降低持续时间对安全参数无影响。EOT时iPTH降低程度也与CKD进展较慢相关。
在患有SHPT和3 - 4期CKD的患者中，使用ERC治疗持续降低升高的iPTH与eGFR下降速率较慢相关，且未引发安全问题。有必要进行前瞻性试验以证实这一发现。
