Sustained Reduction of Elevated Intact Parathyroid Hormone Concentrations with Extended-Release Calcifediol Slows Chronic Kidney Disease Progression in Secondary Hyperparathyroidism Patients

Chronic kidney disease (CKD) afflicts one in 7 adults (14.3%) in the USA with highest prevalence (18.8%) among the black community [1]. Globally, CKD has an estimated prevalence of 13.4% [2], representing nearly 850 million individuals [3]. CKD is a progressive disease [4], causing many individuals with non-dialysis (ND) CKD to eventually require kidney transplantation or regular dialysis. Key risk factors for CKD include aging [2, 5], obesity [6], hypertension [7], and adult-onset diabetes [7]. Human and healthcare costs related to CKD represent a significant economic burden, which increases with disease severity [8, 9], highlighting an urgent need to forestall CKD progression.

Secondary hyperparathyroidism (SHPT) develops as CKD advances. It is characterized by elevated parathyroid hormone (PTH) concentrations, mineral and bone disease, and associated cardiovascular disease, which is the main cause of morbidity and mortality in CKD [10]. Persistently elevated PTH in ND patients may be nephrotoxic [11, 12] and associated with accelerated progression of kidney disease [13]. A retrospective study of 5,000 Italian adults with ND-CKD [14] concluded that dialysis onset was more likely in those with SHPT and that their healthcare costs were greater. Similar findings have been reported from other studies in Italy [15], Spain [16], Germany [17], Sweden [18], and the USA [19‒22], consistent with the conclusion that PTH is a uremic toxin that drives CKD progression [11, 12, 23].

SHPT is exacerbated by vitamin D insufficiency (VDI), defined as serum total 25-hydroxyvitamin D (25D) below 30 ng/mL [24]. Low 25D levels limit production of 1,25-dihydroxyvitamin D (1,25D), the active vitamin D hormone, in kidneys [25] and other tissues containing cytochrome P450 25D-1α-hydroxylase (CYP27B1) [26]. Inadequate levels of circulating and intracellular 1,25D promote PTH secretion and reduce intestinal calcium absorption, the latter increasing the risk of hypocalcemia and further elevating PTH secretion [27].

Supplementation with oral cholecalciferol (vitamin D₃) or ergocalciferol (vitamin D₂) is suggested by clinical practice guidelines [28‒30] to address SHPT arising from VDI and has become the standard-of-care despite the lack of evidence that supplementation effectively lowers elevated PTH in ND-CKD [31]. The latest guideline [30] does not specify a PTH target due to the absence of supporting randomized clinical trial (RCT) data, but comments that modest PTH increases may be an appropriate adaptive response to declining estimated glomerular filtration rate (eGFR).

The present study examines, for the first time, whether effective and sustained intact PTH (iPTH) reduction provides a clinically meaningful benefit to ND-CKD patients with SHPT. Specifically, it evaluates the hypothesis that sustained iPTH reduction can reduce the nephrotoxic impact of SHPT and forestall CKD progression using clinical trial data from ND-CKD patients treated daily for 1 year with oral extended-release calcifediol (ERC), approved as Rayaldee™ in the USA and Europe for treating SHPT [32].

Pooled data from two US multicenter studies with ERC were evaluated post hoc to assess the potential impact of sustained plasma iPTH reduction on CKD progression. These studies adhered to the Declaration of Helsinki; informed consent was obtained from all study participants, and protocols were approved by Schulman Associates IRB (Cincinnati, OH, USA).

These two studies, NCT01651000 (registration date July 23, 2012) and NCT01704079 (registration date June 10, 2012), were conducted concurrently between December 2012 and January 2014 with identical randomized, double-blind, placebo-controlled designs. At enrollment, the 429 participants had plasma iPTH ≥85 to <500 pg/mL, eGFR ≥15 to <60 mL/min/1.73 m², serum total 25D ≥10 to <30 ng/mL, and no macroalbuminuria (>3 mg/mg creatinine). They were stratified 1:1 by CKD stage and randomized 2:1 to receive a daily bedtime dose of oral ERC (30 μg) or matching placebo for 12 weeks, followed by 14 weeks of either 30 or 60 μg/day of ERC (or placebo) according to titration rules intended to produce a ≥30% reduction in iPTH (primary efficacy endpoint) while minimizing safety concerns.

Participants who completed either of these two RCTs could elect to join, without interruption, an open-label extension study, NCT 02282813 (registration date October 31, 2014), during which ERC (but not placebo) was administered for additional 26 weeks, with similar dose titration to 60 μg/day allowed at week 38. The 126 participants who completed 52 weeks of ERC treatment are the focus of the present study.

Measurements of 25D (DiaSorin), calcium (corrected for low albumin), phosphorus, and iPTH (Roche Elecsys) were obtained at baseline (BL) and at biweekly or monthly intervals. Measurements of eGFR (MDRD equation), spot urine albumin-to-creatinine ratio (uACR), 1,25D (IDS), fibroblast growth factor-23 (FGF23; Millipore), and bone turnover markers (BTMs) were obtained at BL and the subsequent four quarterly intervals. Monitored BTMs were bone-specific alkaline phosphatase (Quidel), collagen type 1 C-telopeptide (Roche Cobas), intact procollagen type 1 N-terminal propeptide (Roche Cobas), and total alkaline phosphatase (Roche Cobas). Further details of these studies have been published elsewhere [32‒34].

The 126 participants were grouped into two categories depending on achievement of a sustained mean iPTH reduction of ≥30% (vs. pretreatment BL) at both week 38 (mean of data obtained at weeks 34 through 38) and week 52 (mean of weeks 48 through 52) of the 1-year treatment period. Observed differences between these categories were evaluated by t test or one-way ANOVA followed by Tukey’s test of the means.

Demographic characteristics of the 126 participants who completed 1 year of treatment with ERC (30 or 60 μg/day) are summarized in Table 1, in aggregate and by iPTH reduction category. A total of 51 participants (40.5%) achieved a mean iPTH reduction of ≥30% (vs. pretreatment BL) that was sustained over the last 2 quarters of the treatment period while 75 (59.5%) did not. Participants in both categories were similar in age, balanced for gender, race, and Hispanic ethnicity, had similar utilization of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and had mean BMI above 30 kg/m², with those in the latter category having a greater mean BMI (p < 0.05).

Clinical characteristics for these participants at BL and end of treatment (EOT) are summarized in Table 2, in aggregate and by iPTH reduction category. Participants in both categories had similar BL concentrations for all characteristics except for procollagen type 1 N-terminal propeptide which was 31% higher in participants who did not achieve sustained iPTH reductions (p < 0.01). Serum total 25D rose with ERC treatment from 20.5 ± 0.5 (SE) to 79.0 ± 2.3 ng/mL (p < 0.001). Most participants (73%) were titrated from 30 to 60 μg/day after 12 weeks, as were a few more after 38 weeks. At EOT, serum 25D averaged 17.0 ng/mL higher (p < 0.001) in participants who achieved sustained iPTH reductions of ≥30% (Fig. 1a). Serum 1,25D rose with ERC treatment by 10.1 ± 1.8 pg/mL (from 34.9 ± 1.2; p < 0.001), serum calcium by 0.3 ± 0.03 mg/dL (from 9.2 ± 0.03; p < 0.001), serum phosphorus by 0.2 ± 0.05 mg/dL (from 3.80 ± 0.05; p < 0.01), serum FGF23 by 29.7 ± 14.8 pg/mL (from 32.3 ± 2.8; p < 0.05; one participant’s values rose from 57 to 1,488), and all BTMs improved (p < 0.01). Similar changes in these parameters were observed in both categories. No change during ERC treatment was observed in mean uACR for the full group of participants.

Plasma iPTH decreased by 24.3% from 143.8 ± 5.8 to 108.8 ± 7.2 pg/mL, and reached concentrations that averaged 67.8 pg/mL lower in the category achieving sustained iPTH reductions of ≥30% (Fig. 1b). In the other category comprised of 75 participants, 45 achieved iPTH reductions of any magnitude that were sustained over the last 2 quarters, of which 15 and 18 achieved at least 20% and 10% reductions, respectively. Another 30 participants did not exhibit an iPTH reduction in both of the last 2 quarters.

The average decline in eGFR in the 126 participants was 2.2 ± 0.5 mL/min/1.73 m² from 30.7 ± 0.8 at BL to 28.5 ± 1.1 at EOT (Fig. 2a). The mean 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%) compared to 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 final 2 quarters of treatment (5.4 ± 0.89; 20.9 ± 3.4%). Analysis of mean decreases in eGFR by degree of iPTH reduction at EOT in all participants indicated that reductions of ≥30% were associated with near stabilization of CKD progression, while reductions of <30% were associated with the higher rates of eGFR decline (Fig. 2b). The duration of iPTH reduction had no apparent impact on 52-week changes in mean serum calcium, phosphorus, FGF23, episodes of BTM oversuppression, hypercalcemia (confirmed serum calcium >10.3 mg/dL), hyperphosphatemia (confirmed serum phosphorus >5.5 mg/dL), or hypercalciuria (urine calcium to creatinine ratio of >200), or rates of adverse events.

This study examined whether effective and sustained iPTH reduction with ERC could slow CKD progression using a post hoc analysis of pooled clinical trial data in ND-CKD patients with SHPT. It showed that study participants who achieved iPTH reductions of at least 30% (from pretreatment BL) for the last 2 quarters of a 52-week treatment period experienced minimal decreases in eGFR, averaging 0.6 ± 0.8 mL/min/1.73 m². In contrast, participants who did not achieve this level of iPTH control experienced more than a 5-fold greater decrease in eGFR, averaging 3.2 ± 0.7. This outcome was unaffected by use of the MDRD or CKD-EPI (without race correction) equation. Intermediate degrees of iPTH reduction were associated with proportionally slower eGFR declines. Duration of iPTH reduction of ≥30% was not associated with increases in serum calcium, phosphorus, or FGF23, episodes of BTM oversuppression, hypercalcemia, hyperphosphatemia, hypercalciuria, or rates of adverse events.

Results of the present analysis are consistent with previous observational studies examining a possible association between SHPT and rate of kidney disease progression in ND-CKD patients. A prospective study in Spain [13] of 1,283 adults with ND-CKD reported that the risk of progression (defined as a ≥30% decrease in eGFR or onset of dialysis) during a 2-year observation period was higher in those with diagnosed SHPT (PTH concentrations >70 for stage 3, >110 for stage 4, or >300 pg/mL for stage 5 [28]). A similar study of 2,556 adults in Sweden [18] reported that SHPT (PTH concentrations of 95–168 pg/mL) was associated with a 5-fold higher risk of progression (defined as a doubling of serum creatinine or onset of dialysis). Rates of GFR decline and cumulative incidence of end-stage kidney disease were greater with higher PTH concentrations during prospective long-term follow-up (median of 7.9 years) of 420 US patients participating in the African American Study of Kidney Disease and Hypertension [21]. A retrospective study in Spain [16] of 125 elderly adults with stage 4–5 CKD concluded that the rates of eGFR decline over a 5-year follow-up period were greater with high PTH concentrations (>161 pg/mL in stage 4, >208 in stage 5) and that stabilization of CKD progression was associated with a median PTH concentration of 114 pg/mL. Analysis of repeated PTH measurements over 3 years in 729 Italian adults with ND-CKD [15] supported the conclusion that high PTH concentrations accelerated the progression of renal disease. A similar study in Italy [14] of 5,034 adults with ND-CKD reported that the incident dialysis rate was 5.7-fold higher with SHPT (PTH values ≥85 pg/mL), indicating a possible link between duration of high PTH exposure and clinical outcomes. Retrospective analyses of insurance claims for 66,644 adult ND-CKD patients [19] and 703 adult diabetic ND-CKD patients [20] in the USA, and 3,346 stage 3–4 CKD patients in Germany [17] found that SHPT (defined by diagnosis code) was associated with faster rates of progression and higher costs of care during observation over 2–6 years.

Clinical practice guidelines support the management of SHPT in ND-CKD patients by correcting underlying VDI using treatment strategies recommended for the general population [24, 28‒30]. Such strategies consist of administering oral cholecalciferol or ergocalciferol in an attempt to restore serum 25D levels to targets of 20 or 30 ng/mL [24, 28, 35]. However, RCTs have demonstrated that the target for 25D in ND-CKD patients should be at least 50 ng/mL in order to significantly lower elevated iPTH [34]. Interventional and real-world studies have documented the limited ability of dietary supplements to raise serum 25D to even 30 ng/mL in these patients and their lack of effectiveness in lowering elevated PTH [30, 31, 36‒40]. Most CKD patients are overweight [41]. Dietary vitamin D supplements, being highly fat-soluble, accumulate preferentially in adipose tissue [42]. Supplements have low affinities for the serum-based vitamin D binding protein and, therefore, are poorly drawn out of adipose tissue into circulation for hepatic activation [42]. Further, hepatic 25-hydroxylase activity is reduced in both obesity and CKD [43], blunting the intended elevation of serum total 25D.

Calcifediol, in contrast, requires no hepatic activation, is more water soluble, and avidly binds the circulating vitamin D binding protein, reducing its accumulation in adipose tissue and enabling its access to the kidney and other tissues containing 25D-1α-hydroxylase (CYP27B1) for endocrine and intracrine conversion to calcitriol (1,25D₃), the active hormone [44, 45]. Due to these advantages and its slow-release formulation, ERC successfully increased serum 25D by 58.5 ± 2.3 ng/mL in the present study despite participants having a mean BMI of 35.9 ± 0.8 kg/m².

In the present study, serum total 25D levels were 17 ng/mL higher at EOT in participants who achieved sustained iPTH reductions of ≥30 ng/mL compared with those who did not, probably because their average BMI was 10.4% lower (33.6 ± 1.0 vs. 37.5 ± 1.0 kg/m²). Higher dosages of ERC were likely needed to increase serum 25D exposure in participants with higher BMI. Achieving iPTH reductions of ≥30% with ERC requires sufficient elevation of circulating 25D to raise intracellular calcitriol to concentrations that enable greater parathyroid vitamin D receptor activation. ERC doses above 60 μg/day may be needed for many obese CKD patients and will be the subject of further clinical studies.

Gradual delivery of calcifediol with ERC has been shown to cause minimal suppression of CYP27B1 and minimal upregulation of CYP24A1, the vitamin D catabolic enzyme, fostering intracrine production of calcitriol and control of SHPT despite the loss of renal CYP27B1 in advancing CKD. Extra-renal calcitriol production, which appears to require serum 25D levels ≥50 ng/mL [34] and has been documented in anephric patients [46], is the likely explanation for effective iPTH reduction with ERC despite declining eGFR. Elevation of 25D to levels at or above this threshold is effective for reducing both iPTH and BTMs, as seen in the current and previous study [34], with higher levels required for increasing disease severity.

Immediate-release calcifediol (IRC) upregulates the expression of CYP24A1 [47], which inhibits intracrine calcitriol production, the long-term safety consequences of which are unknown and need to be addressed. A recent clinical comparison of IRC and ERC in ND-CKD patients with SHPT and VDI [48] demonstrated only limited iPTH reduction with IRC. Upregulation of CYP24A1 may explain, in part, the development of parathyroid insensitivity or resistance to IRC, calcitriol, and its 1α-hydroxylated analogues [47]. Ineffective supplementation with cholecalciferol, ergocalciferol, or IRC allows SHPT to progress [37] and PTH to reach concentrations that cannot be readily controlled. Ineffective intervention squanders an opportunity for early and effective PTH reduction with ERC and makes active vitamin D hormone therapy inevitable, despite cautionary guidance on the latter from KDIGO [30].

The present study suggests that elevated iPTH is nephrotoxic. Evidence that PTH is a uremic toxin has been reviewed elsewhere [11, 12], with the mechanism of toxicity likely being PTH-mediated elevation of cytosolic calcium, leading to organ dysfunction [23]. It also suggests that 25D acts directly to reduce renal inflammation, oxidative stress [49, 50], and fibrosis [51], thereby stabilizing eGFR.

A major limitation of the present analysis is the unavoidable post hoc evaluation of the pooled clinical data. Confirmation of these results will require a prospective trial with endpoints addressing elevated iPTH reduction and control and CKD progression. Additional limitations include small sample size, short duration of follow-up, and the potential impact of confounding factors on the reported results such as minor differences in RAAS blockade use and in BL uACR.

In conclusion, this post hoc analysis of clinical trial data shows that sustained reduction of elevated iPTH with ERC treatment was associated with slower rates of eGFR decline in ND-CKD patients diagnosed with SHPT without raising safety concerns. A prospective RCT is warranted to confirm these findings.

The authors would like to acknowledge critical reviews of the manuscript by Dawn Wheeler and Dr. Joel Melnick, and suggestions concerning its content from Dr. Eleanor Lederer. We would also like to acknowledge helpful comments from Drs. Anjay Rastogi, Sagar Nigwekar, and Jordi Bover.

Participants included in the clinical studies described in this article gave written informed consent. Studies were conducted in compliance with the principles of the Declaration of Helsinki. The protocols were reviewed and approved by Schulman Associates IRB (now known as Advarra). For studies NCT0165100 and NCT01704079, the protocol reference numbers were 201206175 and 2021207775; for study NCT02282813, the protocol reference number was 201301591.

Five authors (C.W.B., A.A., S.A.S., J.C., and N.P.) are full-time employees of OPKO Health and have no other conflicts of interest to disclose. S.M.S. is a consultant to OPKO Health.

This study was supported by OPKO Health Inc.

C.W.B. and S.M.S. designed the studies. J.C. and S.A.S. carried out data analysis and preparation of the figures. C.W.B., A.A., and S.M.S. drafted the initial version of the manuscript. All authors (C.W.B., A.A., S.A.S., J.C., N.P., K.C.N., and S.M.S.) reviewed, edited, and approved the final version.

The data that support the findings of this study are not publicly available due to contained information that could compromise the privacy of research participants, but they are available (in redacted form, as applicable) from the corresponding author (S.A.S.) upon reasonable request.