Abstract

INTRODUCTION

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).

METHODS

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.

RESULTS

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.

CONCLUSION

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.

MeSH

Kidney Diseases, Pilots, Serum, Vitamins, Kidney, Hormones, Nephrology, Calcium, Therapeutics, Calcifediol, Hyperparathyroidism, Hyperparathyroidism, Secondary

Cited by

• High-dose extended-release calcifediol successfully treated advanced secondary hyperparathyroidism in an end-stage kidney disease patient: a case report. BMC Nephrol, 2025