Credit: Original article published here.
By 2040, chronic kidney disease (CKD) is projected to be one of the top four leading causes of potential years of life lost. CKD is associated with various comorbidities and complications, including secondary hyperparathyroidism (SHPT) and vitamin D insufficiency (VDI). As patients experience decline in kidney function, there are significant alterations in the metabolism of calcium, phosphorus, and vitamin D that cause increased production and secretion of parathyroid hormone (PTH).
The combination of decreased kidney function, mineral abnormalities, and high rates of comorbidities are associated with reduced quality of life for many patients. SHPT develops as a result of abnormalities in these parameters. Low levels of serum total 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D play a major role in the progression of SHPT.
Concurrent diagnoses of CKD and SHPT have been linked to increased risk of progression of kidney disease, cardiovascular disease, and mortality. Patients with CKD and SHPT have significantly higher medical costs and use of health care resources compared with patients with CKD alone. Poor vitamin D status and elevated levels of PTH commonly occur in patients with stage 3 to 5 CKD, and can emerge as early as stage 2. Early and sustained control of SHPT is necessary to bring PTH, 25D, calcium, phosphorus, and other metabolic parameters into balance.
In adults with stage 3 to 4 CKD and vitamin D insufficiency, standard treatment includes extended-release calcifediol (ERC), active vitamin D hormones and analogs (AVD), and nutritional vitamin D (NVD). Clinical trials assessing the effectiveness of these therapies for increasing serum total 25D and reducing elevated PTH have shown varying results.
Michael J. Germain, MD, and colleagues conducted a retrospective chart review designed to examine real-world experience of ERC and other vitamin D therapies in increasing 25D and reducing PTH. Results of the review were reported in BMC Nephrology [doi.org/10.1186/s12882-022-02993-3].
The review included the medical records of 376 adult patients with stage 3 to 4 CKD and a history of SHPT and VDI from 15 nephrology clinics in the United States for up to 1 year prior to and following initiation of ERC, AVD, or NVD. Key study variables were patient demographics, concomitant use of medications, and laboratory data.
Mean age of the study cohort was 69.5 years, with sex and racial distributions representative of the US CKD population. A total of 376 patients were enrolled. Enrolled patients were grouped by treatment into three cohorts: ERC (n=174), AVD (n=55), and NVD (n=147). The cohorts were similar in mean baseline levels for serum 25D (18.8-23.5 ng/mL), calcium (9.1-9.3 mg/dL), phosphorous (3.7-3.8 mg/dL), and estimated glomerular filtration rate (eGFR) (30.3-35.7 mL/min/1.73 m2). Mean PTH at baseline was 181.4 pg/mL for the ERC cohort versus 156.9 pg/mL for the AVD cohort and 134.8 pg/mL (P<.001) for the NVD cohort. Mean follow-up during treatment ranged from 20.0 to 28.8 weeks.
Of the overall cohort of 376 patients, 46.3% (n=174) initiated treatment with ERC (99.4% at a daily dose of 30 mcg); 14.6% (n=55) initiated treatment with AVD (80% received calcitriol at 0.25 mcg/day, 11% received calcitriol at 0.50 mcg/day, 7% received doxercalciferol at 2.5 mcg/day, and 2% received paricalcitol at 1.0 mcg/day); and 39.1% (n=147) initiated treatment with NVD (weekly oral ergocalciferol [n=97] or cholecalciferol [n=50] at doses of ≥50,000 IU [64.7%], 14000 to <50,000 IU [23.1%], or 5000 to <14,000 IU [12.2%} for ≥7 months [55.8%], 4-6 months [19%], or 103 months [25.2%]).
In the overall cohort, mean body mass index (BMI) was 32.8 kg/m2, 50.8% were female, 88.8% were non-Hispanic, and 64.6% were White. BMI was highest in the ERC cohort. The ERC and AVD cohorts had more patients with CVD stage 4 than patients with stage 3; the reverse was true in the NVD cohort.
Most prescriptions had durations of >6 months. The mean observed prescription length of ERC was 63.5 weeks versus 51.3 weeks for AVD and 41.5 weeks for NVD. A small percentage of patients in the ERC cohort (1.7%) up-titrated dose; patients in the AVD and NVD cohorts maintained a constant dose for the duration of the study.
In the ERC cohort, treatment with ERC raised 25D by 23.7 ng/mL (P<.001) and decreased PTH by 34.1 pg/mL (P<.001). There was no significant impact on serum calcium and phosphorus. There was a downward trend in serum total alkaline phosphatase. There was a decrease in eGFR of 3.1 mL/min/1.73 m2. Mean follow-up for those parameters ranged from 23.4 to 28.8 weeks. Normalized for the duration of the follow-up (mean 28.1 weeks), the mean decrease in eGFR per patient-week was 0.11 mL/min/1.73 m2.
In the AVD cohort, serum 25D rose by 5.5 ng/mL with no statistically significant impact on PTH and serum phosphorous levels. There was a downward trend in serum total alkaline phosphatase. There was a decrease in eGFR of 1.6 min/mL/1.73 m2. Normalized for duration of the follow-up (mean 21.4 weeks), the mean eGFR decrease per patent-week was 0.08 mL/min/1.73 m2.
In the NVD cohort, serum 25D rose by 9.7 ng/mL with no significant impact on PTH or serum calcium and phosphorous levels. There was a decrease in eGFR of 1.2 mL/min/1.73 m2. Normalized for the duration of the follow-up (mean 20.0 weeks), the mean eGFR per patient-week decrease was 0.07 mL/min/1.73 m2.
Limitations to the study cited by the authors included insufficient duration to assess end points related to cardiovascualr disease, fractures, hospitalization rates, and mortality, as well as the possibility of selection bias.
In summary, the authors said, “Results from the current study highlight ERC’s strong potential to successfully address unmet treatment needs associated with AVD and NVD in patents with SHPT, stage 3-4 CKD, and VDI. These real-world data demonstrated ERC’s ability to reliably increase serum 25D and reduce elevated PTH levels without significant negative clinical impact on serum calcium and phosphorous levels. Future research into factors influencing clinical patient follow-up and dose titration practices, as well as what patient-related characteristics are influential in treatment outcomes, can further contribute toward informing optimal SHPT management and treatment practices to improve clinical effectiveness and safety.”
Takeaway Points
- Researchers reported results of a retrospective chart review to assess real-world experience with extended-release calcifediol (ERC) and other vitamin D therapies in the management of secondary hyperparathyroidism (SHPT).
- Patients were separated into three treatment groups: those receiving ERC; those receiving active vitamin D hormones and analogs, and those receiving nutritional vitamin D.
- Serum total 25-hydroxyvitamin D rose in all three cohorts; the highest increase with in the ERC cohort. Parathyroid hormone declined with ERC treatment but remained unchanged in the other two cohorts.
