|Year : 2015 | Volume
| Issue : 6 | Page : 1135-1141
|Tolerance and efficacy of a low dose of the calcimimetic agent cinacalcet in controlling moderate to severe secondary hyperparathyroidism in hemodialysis patients
Salah O Bashir1, Hayder A Omer2, Mahmoud A Aamer3, Rashid Somialy3, Mohamed D Morsy1
1 Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
2 Department of Nephrology, College of Medicine, King Khalid University, Abha, Saudi Arabia
3 Department of Nephrology, Aseer Central Hospital, Abha, Saudi Arabia
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|Date of Web Publication||30-Oct-2015|
| Abstract|| |
Secondary hyperparathyroidism is almost a constant feature in chronic kidney disease (CKD) patients maintained on hemodialysis (HD). Calcimimetic agents appear to offer an alternative to surgery in controlling secondary hyperparathyroidism in these patients. Recent studies provide conflicting data on the benefits, efficacy and tolerance of cinacalcet as first-line therapy for the treatment of secondary hyperparathyroidism in CKD. This study was designed to investigate the efficacy and tolerance of a low dose of the calcimimetic agent cinacalcet in patients on long-term HD having moderate to severe secondary hyperparathyroidism. Twentyfive adult male patients on HD for more than three years were included in the study. All had moderate to severe secondary hyperparathyroidism with serum intact parathyroid hormone (iPTH) >50 pmol/L, resistant to conventional treatment. We used the targets of Chronic Kidney Disease: Outcomes Quality Initiative (K/DOQI) clinical guidelines as optimal target of serum iPTH, calcium and phosphate. Patients were administered cinacalcet as a single oral daily dose of 30 mg and were followed-up for six months. Cinacalcet treatment for six months resulted in a significant reduction in the serum phosphate and iPTH levels while the serum calcium levels remained unchanged. Thirty-six percent of the patients attained the recommended serum iPTH levels, 40% achieved significant reduction of the serum iPTH levels and 24% showed no favorable response. Only one patient dropped out because of severe gastrointestinal symptoms. Our results suggest that treatment of CKD patients, having moderate to severe secondary hyperparathyroidism, with low-dose cinacalcet is effective and well tolerated.
|How to cite this article:|
Bashir SO, Omer HA, Aamer MA, Somialy R, Morsy MD. Tolerance and efficacy of a low dose of the calcimimetic agent cinacalcet in controlling moderate to severe secondary hyperparathyroidism in hemodialysis patients. Saudi J Kidney Dis Transpl 2015;26:1135-41
|How to cite this URL:|
Bashir SO, Omer HA, Aamer MA, Somialy R, Morsy MD. Tolerance and efficacy of a low dose of the calcimimetic agent cinacalcet in controlling moderate to severe secondary hyperparathyroidism in hemodialysis patients. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2021 Nov 29];26:1135-41. Available from: https://www.sjkdt.org/text.asp?2015/26/6/1135/168583
| Introduction|| |
Secondary hyperparathyroidism is almost a constant feature in chronic kidney disease (CKD) patients maintained on dialysis.  The pathophysiology of the problem involves impaired excretion of phosphate, impaired reabsorption of calcium as well as reduced hydroxylation of 25-hydroxy-cholecalciferol into calcitriol, the active form of vitamin D. 
Parathyroid cells rarely divide under normal physiological conditions; however, proliferation of the cells can occur in response to mitogenic stimuli such as hypocalcaemia, calcitriol deficiency and phosphorus retention, as is the case in CKD. , Development of parathyroid hyperplasia is associated with downregulation of vitamin D receptors (VDR) and calcium-sensing receptors (CaSR). 
The Chronic Kidney Disease: Outcomes Quality Initiative (KDOQI) standards were formulated in an attempt to minimize the morbidity and mortality associated with abnormal mineral metabolism, abnormal bone processing and possible cardiovascular toxicity and vascular and extra-skeletal calcification.  These practice guidelines provide the best current standards in the evaluation and management of chronic kidney disease-mineral and bone disorder (CKD-MBD).
The goal of treatment is to achieve normal levels of phosphate, parathyroid hormone (PTH) and calcium. Conventional therapy includes dietary modification to reduce phosphate intake, the use of phosphate binders, hydroxylated vitamin D sterols (calcitriol, alfacalcidol) or the synthetic vitamin D analogue paricalcitol and modification of the dialysis regimen. In severe hyperparathyroidism, parathyroidectomy is required.  Around 10-30% of the patients with more than 10 years of hemodialysis (HD) end up requiring parathyroidectomy. 
Within the last 10 years, calcimimetic agents were offered as an alternative approach to controlling hyperparathyroidism. The most potent factor controlling PTH secretion is the interaction of ionized serum calcium with the CaSR in the parathyroid glandular cell membrane.  Calcimimetic agents increase the sensitivity of the CaSR to extracellular calcium ions,  thereby inhibiting the release of PTH within few hours after administration.  Cinacalcet is currently the only approved calcimimetic drug. Numerous prospective randomized studies in patients on maintenance HD with mild to severe hyperparathyroidism have found that the administration of cinacalcet produces a dose-dependent reduction in the plasma PTH concentration and a decrease in the levels of calcium and phosphate. ,, The use of cinacalcet in CKD patients on dialysis became widespread. However, the overall benefit to the patients is still disputed. Recent large-scale studies generated conflicting evidence on the benefits and clinical outcomes. ,, The EVOLVE large multicenter study concluded that cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients with moderate to severe secondary hyperparathyroidism who were undergoing dialysis.  On the other hand, current clinical practice analysis across Europe has shown that treatment with cinacalcet provides marked improvement in biochemical parameters, achieving the KDOQI targets for serum levels of intact PTH (iPTH), phosphorus, calcium and Ca × P.  These studies thus raised serious concerns over the tolerance and safety of the drug.
The aim of the present study was to determine the efficacy and tolerance of low-dose cinacalcet in controlling serum iPTH levels and avoiding surgical intervention in HD patients with moderate to severe hyperparathyroidism who were resistant to conventional therapies.
| Subjects and Methods|| |
This study was approved by the Ethical Committee of the College of Medicine, King Khalid University, Saudi Arabia and followed the instructions in accordance with the ethical standards of the responsible committee on human experimentation and was adherent to the Helsinki Declaration of 1975, revised in 2000 (available at http://www.wma.net/e/policy/17-c_e.html). Also, an informed consent was obtained from all the patients.
Twenty-five adult male patients with endstage renal disease, who had been on maintenance HD for more than three years, were included in this prospective trial. All patients were recruited from the dialysis center of the Asser General Hospital, Abha, Saudi Arabia. The patients included in the current study had persistently elevated serum iPTH levels despite conventional therapy with calcium, vitamin D sterols and phosphate binders. The primary eligibility criteria were stable medical condition and moderate to severe secondary hyperparathyroidism with serum iPTH ≥50 pmol/L. The serum iPTH levels were established by three measurements obtained within a 30-day screening period. The KDOQI standards are: mean PTH <31.8 pmol/L (300 pg/ mL), mean serum calcium 2.10-2.37 mmol/L, mean serum phosphate 1.13-1.78 mmol/L and mean Ca × P <4.44 mmol 2 /L 2 .
All patients were on HD treatment three times per week (4 h/session). Polysulfone dialyzers and bicarbonate bath with dialysate calcium concentration of 1.25 mmol/L and sodium concentration of 136 mmol/L were used for dialysis. All patients were maintained on calcium carbonate (600-1200 mg po TID), calcitrol (PO) (0.25-1 mg) and phosphate binders (Renagel 800 mg ×3) and they were receiving recombinant erythropoietin intravenously two to three times post-dialysis.
The treatment protocol consisted of a 24week treatment period with cinacalcet 30 mg with the main meal as a single daily oral dose. The drug was taken with the meal to minimize gastrointestinal symptoms. The dose of the active vitamin D derivative was maintained at the lowest level (alfacalcidol, 0.25 μg/day) during the study period. Symptoms and signs observed by the investigators or reported by the subject directly or in response to a leading question were noted. The calcimimetic agent cinacalcet (Mimpara R/Sensipar R; Amgen Inc., Thousand Oaks, CA, USA) was administered as a single oral daily dose of 30 mg for six months.
Serum iPTH, serum calcium and phosphorus levels were measured at each study visit before HD, approximately 24 h after the preceding dose. Serum iPTH was measured every month using the Coat-A-count immune-radiometric assay method (Diagnostic Products Corporation, Los Angeles, CA, USA).
| Statistical analysis|| |
Data were analyzed using the Kolmogrov- Smirnov Z test to test whether data were normally distributed or not. Because the data were not normally distributed, the Wilcoxon Signed Ranks test was used. Statistical significance was accepted at the level of P <0.05.
Results were expressed as median. Statistical analysis was performed with the SPSS statistical package for windows (SPSS version 13.0; SPSS Inc., Chicago, IL, USA).
| Results|| |
[Table 1] shows the overall demographic and biochemical data of the patients.
|Table 1: Biochemical data of patients pre- and post-treatment with cinacalcet for 6 months.|
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The serum calcium levels were in the normal range in all patients at the start of the study and did not change significantly after six months of treatment (2.38 and 2.25 mmol/L, respectively).
The serum phosphate values were also within the recommended range in all study patients at the start of therapy (1.62 mmol/L), and showed a significant decrease at the end of the study (1.55 mmol/L).
The mean serum iPTH levels decreased significantly by the end of the study period (94.5 and 57.75 pmol/L, respectively) (P <0.001).
The target serum iPTH levels were achieved in nine patients (36%). Of the 15 patients who did not achieve the target level, ten (40%) had a significant decrease in serum iPTH, ranging from 16% to 53% [Figure 1] and [Figure 2]. Five patients (20%) showed no change or an increase in their serum iPTH levels. One patient (4%) dropped out because of severe gastrointestinal symptoms.
|Figure 1: Percentages of the different response groups in relation to target levels of serum intact parathyroid hormone (iPTH) after 6 months of cinacalcet treatment.|
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|Figure 2: Percentage reduction of serum intact parathyroid hormone (iPTH) in the different response groups after 6 months of cinacalcet therapy.|
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The percentage of drop of the mean iPTH levels in patients who achieved the target level was about 75%. In the partial response group, the iPTH dropped by about 38% and in the non-responders, there was an increase in iPTH of about 6% above the target level [Figure 2].
| Discussion|| |
Management of secondary hyperparathyroidism is one of the challenging aspects of caring for a patient with CKD. The efficacy and safety of cinacalcet for the control of secondary hyperparathyroidism in CKD is currently being revaluated in lieu of recent studies questioning its overall efficacy and tolerance.  The patients included in the current study had persistently high serum iPTH levels despite conventional therapy with calcium, vitamin D sterols and phosphate binders. Cinacalcet was introduced to avoid or delay surgical intervention. Cinacalcet treatment resulted in significant lowering of the serum iPTH levels. Thirty-six percent of patients attained the target serum iPTH levels, and an additional 40% had reduction of their serum iPTH levels [Figure 1] between 16% and 53% of their baseline levels [Figure 2]. In comparison, a multicenter Spanish study reported achievement of target levels of serum iPTH in 32.5% of patients,  and the equivalent figure from a pan-European study was 28%.  Comparing the demographic data between responders and non-responders with regard to the original pathology, age or duration on dialysis did not reveal any contributing factors. Al Saran et al and Al-Hwiesh et al have reported similar findings. ,
The most commonly reported side-effects of cinacalcet treatment are increased risk of hypocalcemia, nausea and diarrhea. ,, Several multicenter studies in dialysis patients with secondary hyperparathyroidism have reported severe adverse effects in 11-18% of patients receiving cinacalcet. ,, However, these studies used higher or multiple daily doses of the drug with titration of the dose up to 180 mg. Our patients had very few sideeffects and cinacalcet had to be stopped in only one case who developed severe vomiting. The hypocalcemic episodes were mild and were managed by adjusting the calcium and vitamin-D supplements. The single low-dose administered with the main daily meal in our study may have reduced the incidence of gastrointestinal upsets. In Saudi patients, Al Saran et al reported adverse side-effects in about 20% of patients administered a daily dose of 120 mg of cinacalcet, whereas AlHilali et al found that a bi-weekly dose was better tolerated and was still as effective as a daily regimen. , It is possible that higher doses could have improved the control of serum iPTH but at the expense of more frequent and more serious side-effects. Even more alarming, a higher incidence of neoplastic events was observed in the EVOLVE study. 
Our study has certain limitations in relation to patient selection and also the follow-up. The study population consisted of patients with moderate to severe hyperparathyroidism rather than the early cases recommended for best response to cinacalcet. However, our aim was to determine whether cinacalcet is still beneficial for those patients by reducing the need of parathyroidectomy. Also, we did not study the impact of treatment on bone changes, incidence of tissue and vascular calcification or mortality. The EVOLVE study showed that cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients with moderate to severe secondary hyperparathyroidism who were undergoing dialysis.  However, the same study found that patients on cinacalcet had prolonged time to first parathyroidectomy compared with the placebo group and a longer time to a first episode of severe, unremitting hyperparathyroidism. Our results support these findings. Similar conclusions were reached by Palmer et al in their meta-analysis of 18 trials.  The surgical and metabolic risks associated with parathyroidectomy in HD patients are well documented. Narayan et al found that cinacalcet was more cost-effective than surgery, especially for patients with a high risk of mortality and in those who would expect to receive a kidney transplant. 
Our study suggests that low-dose cinacalcet is well tolerated and yet effective in controlling moderate to severe secondary hyperparathyroidism in CKD patients. Further studies are needed, with variations in the dose, to formulate clinical practice guidelines that establish the balance between the risks and the benefits of this drug.
| Acknowledgments|| |
The authors would like to acknowledge the much appreciated contribution of Professor Ahmed Mafouz of the Department of Community Medicine, Faculty of Medicine, King Khalid University in the statistical analysis of the data. We would also like to acknowledge the cooperation and advice of Dr. Ibrahim Jubran, head of the Nephrology Unit at the Assir Central Hospital and Director of the King Abd Aziz Daughters Charity Dialysis Center.
Conflict of interest: None declared.
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Salah O Bashir
Department of Physiology, College of Medicine, King Khalid University, Abha
[Figure 1], [Figure 2]
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