Comparison of parathormone lowering effects of paricalcitol and calcitriol in hemodialysis patients

Abstract

BACKGROUND

Parathyroid hormone (PTH) levels may fluctuate in patients undergoing hemodialysis because of changes in calcium, phosphorus, and vitamin D levels. For these patients, the “Kidney Disease: Improving Global Outcomes” clinical practice guidelines recommend PTH levels be maintained in the range of two to nine times of the upper normal limit. Maintaining this balance is critical to prevent renal osteodystrophy. When the severity of hyperparathyroidism exceeds the recommended limits, vitamin D receptor agonists may be used for lowering PTH levels. Paricalcitol, as a biologically active vitamin D analog, is a selective activator of vitamin D responsive pathways. Both calcitriol and paricalcitol can be used as PTH-lowering agents. There is conflicting data about their comparative effectiveness for controlling hyperparathyroidism in patients undergoing hemodialysis and a meta-analysis revealed no differences between the two.

AIM

To give real world data comparing paricalcitol and calcitriol as PTH-lowering agents in patients undergoing hemodialysis.

METHODS

Patients undergoing hemodialysis whose PTH levels exceeded nine times of the upper normal limit were enrolled in the study. Depending on patient preferences, they were either given calcitriol or paricalcitol. Intravenous calcitriol was given 2 μg at the end of each dialysis sessions, and intravenous paricalcitol was administered as 5 μg twice per week. Demographic data, calcium-phosphorus levels, change in PTH levels in 6 months, and ratios of 25% and 50% reductions in PTH levels were compared between the two groups.

RESULTS

A total of 21 patients were enrolled in this comparative study, eight patients received paricalcitol and 13 were prescribed calcitriol. A 50% reduction in PTH levels could be achieved in five patients in the paricalcitol group (62.5%); only one patient in the calcitriol group achieved the same reduction (7.6%). The difference was statistically significant (P = 0.014). However, there was no difference in the ratio of patients who had a 25% reduction in PTH levels (87.5% vs 38.4%; P = 0.067). PTH levels could be maintained in the targeted range in 87.5% of the patients in the paricalcitol group and in 69.2% of the patients in the calcitriol group (P = 0.36). However, PTH could be better suppressed under paricalcitol. Clinically important hyperphosphatemia or hypercalcemia was not observed in either the paricalcitol or the calcitriol groups.

CONCLUSION

Although the PTH lowering effect of paricalcitol is stronger than calcitriol, both may help maintain PTH levels in the targeted range. Paricalcitol may be preferred for patients who have very high levels of PTH because it seems to cause a faster decline. Calcitriol may be preferred for a slower and limited decline. Prospective further studies with larger samples may be needed for a better comparison.

Key Words: Hemodialysis; Parathormone; Calcitriol; Paricalcitol; Vitamin D

Core Tip: Parathormone control has utmost importance for patients undergoing hemodialysis to decrease fracture risk and provide better survival. Although international guidelines recommend keeping parathormone levels between two to nine times of the upper normal limit, new studies provide survival evidence for tighter control. Paricalcitol was found more effective than calcitriol in providing a faster and greater reduction of parathormone. Close monitoring of phosphorus and calcium levels avoided unintended hyperphosphatemia or hypercalcemia with either treatment.

INTRODUCTION

Parathyroid hormone (PTH) levels may fluctuate in patients undergoing hemodialysis because of changes in the metabolism of calcium, phosphorus, and vitamin D[1]. For these patients, the “Kidney Disease: Improving Global Outcomes” (KDIGO) clinical practice guidelines recommend PTH levels be maintained in the range of two to nine times of the upper normal limit[2]. This balance is highly important to prevent renal osteodystrophy and reduce fracture risk. In addition, uncontrolled secondary hyperparathyroidism is associated with increased mortality, mainly through vascular calcifications[3]. For patients with bone pain and increased high bone turn-over markers such as high alkaline phosphatase, the PTH level range may be further narrowed, such as not exceeding seven times of the upper normal limit.

Initial strategies to control secondary hyperparathyroidism include correction of hyperphosphatemia and hypocalcemia[4]. When the severity of hyperparathyroidism exceeds the recommended limits, active vitamin D (i.e., 1,25 dihydroxyvitamin D) -calcitriol may be added to treatment regimens. Paricalcitol, as a biologically active vitamin D analog and a selective activator of vitamin D responsive pathways may also be prescribed[5]. Both calcitriol and paricalcitol can be used as PTH-lowering agents. However, there are conflicting data about their comparative effectiveness for controlling hyperparathyroidism in patients undergoing hemodialysis and a meta-analysis revealed no difference between the two[6]. This study aimed to give real world data comparing paricalcitol and calcitriol as PTH-lowering agents.

MATERIALS AND METHODS

Setting

The study was conducted on patients undergoing hemodialysis at a secondary healthcare center (Bingol State Hospital, Türkiye) with a fully equipped hemodialysis facility. The facility followed up 113 patients undergoing maintenance hemodialysis in the past calendar year.

Patients and eligibility criteria

Patients undergoing hemodialysis who were dialyzed thrice weekly in the previous 3 months, who’s intact PTH (iPTH) levels exceeded nine times of the upper normal limit and received no parathormone-lowering therapy in the previous 3 months were eligible to be enrolled in the study. Inclusion criteria were as follows: Age over 18 and having normal corrected calcium and phosphorus levels in the previous 3 months. Patient with active malignancies, who were hospitalized for any reason in the previous 3 months, prescribed calcimimetics (e.g., cinacalcet) in the previous 3 months or used immunosuppressive agents in the previous 12 months were excluded from the study.

Hemodialysis specifications

Patients received thrice weekly intermittent hemodialysis using 1.25 mmol/L calcium and 2 mmol/L phosphorus baths on Fresenius Medical Care 4008 series hemodialysis machines and high-flux dialyzers. The dialysate bicarbonate concentration was 36 mmol/L. Low-molecular-weight heparin was used for anticoagulation. Ultrafiltration was adjusted according to volume status and the dry weight of the patients.

Study protocol

Calcitriol or paricalcitol were used as PTH-lowering drugs. After obtaining written informed consent for study participation, patients were provided with comprehensive information about both drugs and assigned to their preferred drug group accordingly. Intravenous calcitriol was given 2 μg at the end of each dialysis sessions, and intravenous paricalcitol was administered as 5 μg twice per week. PTH-lowering effects, including the 25% reduction rate, the 50% reduction rate, and absolute intact PTH levels were compared at the end of the sixth month.

Data collection and patient follow-up

The primary kidney diseases of the patients and their demographic data were extracted from electronic health records. Calcium-phosphorus levels, electrolytes, hemoglobin, albumin, ferritin, C-reactive protein levels, serum lipids, and transaminase levels were measured monthly. Phosphate-binding agents and appropriate calcium supplementation was provided to keep them in the normal range throughout the study. Intact parathormone (intact PTH) levels were checked every 3 months. The change in intact PTH levels after 6 months and the ratios of 25% and 50% reductions were calculated and compared between the two groups.

Statistical analysis

Data are expressed as means ± SD. Continuous variables were compared using the independent samples t-test. Categorical variables were compared using either Pearson’s χ² or Fisher’s exact tests. All tests were performed using technical SPSS for Windows, version 25.0 software (SPSS Inc. Chicago, IL, United States). Two-sided P-values less than 0.05 were accepted as statistically significant.

Power analysis

Given the mean intact PTH levels were 834.5 ± 281.0 vs 560.3 ± 289.3 ng/L for the paricalcitol and calcitriol groups on the day of study inclusion and the assumption that around 50% of the patients receiving paricalcitol would have a 50% of reduction in their intact PTH levels in comparison with around 10% of the patients receiving calcitriol, inclusion of at least eight patients in each group would reach 90% of power with 5% of type 1 error.

Ethics approval

The study was approved by the Institutional Review Board of Provincial Health Directorate (Approval No. 2020-11-30T14_57_30). All patients signed written informed consent forms and the study was performed according to the rules of Declaration of Helsinki.

RESULTS

After the application of inclusion and exclusion criteria to the cohort, a total of 21 (12 males and 9 females) patients were enrolled in this prospective non-randomized open-label comparative study; eight patients received paricalcitol and 13 were prescribed calcitriol. The sex distribution was not different between the groups (the ratio of males was 75% in the paricalcitol group and 46.1% in calcitriol group; P = 0.20). The mean patient age was 59.6 ± 13.7 years and their mean dialysis vintage was 65.4 ± 47.8 months. The patients’ primary kidney diseases were diabetic kidney disease (n = 7, 33.3%), hypertensive nephrosclerosis (n = 5, 23.8%), glomerulonephritis (n = 4, 19.0%), polycystic kidney disease (n = 1, 4.7%) and nephrolithiasis (n = 1, 4.7%). The etiology of end-stage kidney disease was not known for the remaining three patients. Given the limited sample size, ratios of primary kidney diseases were not compared between the groups.

A 50% reduction in intact PTH levels was achieved in five patients in paricalcitol group (62.5%) and one patient of the calcitriol group (7.6%), which was statistically significantly different (P = 0.014). However, there was no statistically significant difference in the ratio of patients who had a 25% reduction in intact PTH levels (87.5% vs 38.4%; P = 0.067). Intact PTH levels could be maintained in the targeted range in 87.5% of patients in paricalcitol group and 69.2% of the patients in calcitriol group (P = 0.36). However, intact PTH was better suppressed under paricalcitol treatment. At the end of month 6, the mean intact PTH levels of patients treated with paricalcitol was 388.5 ± 190.5 ng/L and 533.5 ± 161.6 ng/L for patients treated with calcitriol. The difference did not reach statistical significance, most probably because of the limited sample size. Clinically important hyperphosphatemia or hypercalcemia was not observed in either the paricalcitol or calcitriol groups. Other comparisons of parameters can be found in Table 1.

Table 1 Comparison of the parameters between paricalcitol and calcitriol groups, mean ± SD/n (%).

	Paricalcitol (n = 8)	Calcitriol (n = 13)	P value
Age	58.8 ± 14.5	60.0 ± 13.7	0.85
Male sex	6 (75)	6 (46.1)	0.20
Dialysis vintage (months)	63.0 ± 52.4	68.8 ± 49.9	0.80
Calcium (mg/dL)	9.1 ± 0.4	8.3 ± 0.5	0.005
Phosphorus (mg/dL)	4.1 ± 1.1	4.3 ± 0.8	0.43
PTH (ng/L) (on day 0)	834.5 ± 281.0	560.3 ± 289.3	0.005
PTH (ng/L) (6th month)	388.5 ± 190.5	533.5 ± 161.6	0.076
50% reduction ratio	62.5%	7.6%	0.014
25% reduction ratio	87.5%	38.4%	0.067
Lowering to target range	87.5%	69.2%	0.36
Hemoglobin (g/dL)	11.1 ± 2.0	11.5 ± 1.3	0.67
Albumin (g/dL)	3.9 ± 0.1	3.9 ± 0.25	0.72
CRP (mg/L)	9.8 ± 9.2	4.8 ± 3.4	0.09

PTH: Parathyroid hormone; CRP: C-reactive protein.

DISCUSSION

For patients undergoing hemodialysis, maintaining PTH levels in the targeted range has utmost importance because this will prevent renal osteodystrophy and improve overall survival[7]. Treatment strategies combating renal osteodystrophy should already be applied early in the management of chronic kidney disease and mainly include phosphorus and calcium control[3]. 25-OH vitamin D levels should also be maintained over 30 ng/mL as recommended by a European consensus statement[8].

When patients with chronic kidney disease reach end-stage, secondary hyperparathyroidism may be more remarkable because phosphorus control becomes more difficult at this stage, and patients’ compliance with diet recommendations and drug treatments may not be very good[9]. The KDIGO recommends keeping PTH within two-to-nine times of the upper normal limit, and the higher limit of these range may be more restricted (such as seven times) for patients who most probably have high-turnover renal osteodystrophy. Clues for such a situation are bone pain and/or documented osteopenia. Also, very recently, targeting lower PTH levels was found to be associated with lower cardiovascular mortality[10].

Active vitamin D (calcitriol) or vitamin D analogs (e.g., paricalcitol) are the focus of treatment strategies for lowering PTH because active vitamin D levels also decrease in patients undergoing hemodialysis[11]. However, these agents may have destabilizing effects on phosphorus control and increase calcium levels, thus the calcium-phosphorus balance should be closely monitored when these drugs are prescribed. Keeping calcium and phosphorus in the normal range for a certain period before commencing these drugs may be a protective approach. Accordingly, this study only included patients who had normal calcium-phosphorus levels for 3 months before commencing calcitriol or paricalcitol. Another reason for selecting patients with normal calcium and phosphorus levels was to eliminate their effect on PTH levels. Otherwise, the PTH-lowering effects of paricalcitol and calcitriol could not be accurately compared.

Calcimimetics are another group of drugs that may help to control hyperparathyroidism in patients undergoing dialysis. However, especially for patients with severe hyperparathyroidism, their use as monotherapy is not recommended and they should be add-on options for patients using active vitamin D or vitamin D analogs[12]. Patients using cinacalcet were excluded from the study because we aimed to compare the effects of calcitriol and paricalcitol, and cinacalcet may be synergistic for their effects.

Dosing of calcitriol and paricalcitol is another area of lesser certainty. It is generally started at low doses (e.g., 0.25 μg thrice weekly for calcitriol) and up-titrated according to control of phosphorus and calcium levels. However, given the relatively long dialysis vintage of our patients and their high PTH levels, this study compared higher doses of calcitriol (2 μg thrice weekly) and paricalcitol (5 μg twice weekly). No adverse effects, such as hyperphosphatemia or hypercalcemia, were observed and this was mainly because of close monitoring of electrolytes throughout the study period.

With this prospective comparative study, it was shown that the PTH-lowering effect of paricalcitol was stronger than calcitriol. Such a superiority for paricalcitol could be shown although calcitriol was used in higher doses starting from day 0. When the target range for PTH was accepted as two-to-nine times of the upper normal limit as suggested by the KDIGO, paricalcitol and calcitriol were comparable in reaching the target range. However, allowing PTH to reach nine times of the upper normal limit may not always be an appropriate, especially for patients with signs of high bone turnover. Tighter PTH control might be needed and paricalcitol use may be more appropriate for such a target.

There are few studies comparing paricalcitol and calcitriol in patients undergoing hemodialysis. In one of the largest studies, Teng et al[13] found better survival in patients who used paricalcitol. The PTH-lowering effect of paricalcitol was also better. However, that study was a retrospective study and the mean calcitriol dose was around 1 μg at each administration. Previous studies have shown that paricalcitol results in faster PTH reduction than calcitriol but the drug doses in these studies were not constant throughout the study periods, with up-titration until target PTH reduction was reached[14,15]. By contrast, the present study used paricalcitol and calcitriol in previously defined fixed doses and compared the effect of paricalcitol with relatively higher doses of calcitriol.

Paricalcitol may be preferred for patients with very high levels of intact PTH because it was found to result in a faster decline. Calcitriol may be preferred for a slower and limited decline. For absolute values at the end of the 6^th month, there was no statistically significant difference. Accordingly, either drug may help in controlling hyperparathyroidism. Switching from calcitriol to paricalcitol may be reasonable in patients whose PTH levels cannot be controlled by calcitriol. However, such a response to paricalcitol may depend on the size of the parathyroid gland and previously it was shown that the PTH-lowering effects of paricalcitol may be limited in hyperplastic parathyroid glands[16].

This study has some limitations. First, the sample size is limited. This may result in the study being interpreted as a descriptive investigation rather than an analytical study. However, certain exclusion criteria had to be applied to reach a clinically appropriate group to compare the two drugs. As shared in the methods section, the sample size of the study had enough power to show the difference between the effects of paricalcitol and calcitriol. Also, drugs were prescribed per patients’ preferences. A blind randomization might have provided more reliable data. Bone density scans or bone turnover markers were not checked, thus there were insufficient data to comment about the type of osteodystrophy in these patients. Nevertheless, the real-life data presented herein may help physicians in their prescription decisions when they encounter patients with resistant secondary hyperparathyroidism.

CONCLUSION

Our study showed that paricalcitol was more effective in providing better PTH control. In a meta-analysis of published studies, calcitriol and paricalcitol were comparable in their PTH-lowering effects[6]. However, there is generally heterogeneity in drug doses and follow-up times. Prospective further studies with larger samples and longer follow-ups may be needed for better comparisons.