| Abstract|| |
To determine the efficacy and safety of cinacalcet, a calcimimetic drug that suppress parathyroid hormone (PTH) production, we studied its effect on 20 patients (13 males) on maintenance hemodialysis (HD), 80% of them have persistent high PTH levels (i.e. more than 80 pmol/L), the remaining patients had PTH levels more than 60 pmol/L. Five of 20 (25%) patients dropped out from the study (2 because of severe GIT upset, one showed severe myalgia and arthralgia, one patient due to non compliance and one died at home due to cardiac arrest). The remaining 15 patients (10 males) had a mean age of 40 ± 12.86 years and dialysis duration of 29.13 ± 18.27 months. The follow-up period on cinacalcet was 4 months with a single daily oral dose started with 30 mg/day and increased gradually according to the PTH levels. Nine (60%) patients were on concomitant active vitamin D during the study period with a mean dose of 7.33 ± 3.39 μg/week. There was a significant decrease in the serum PTH levels at the end the study compared to that at the start (46.4 ± 4.7 pmol/L versus 93.3 ± 25.6 pmol/L, respectively, P< 0.000), and the target PTH level (< 31.6 pmol/L) was achieved in 54% of patients. No significant changes in serum Ca and phosphorous levels were observed. We conclude that cinacalcet is an effective therapy to suppress the serum PTH levels and allows favorable management of the serum calcium and phosphorus levels in HD patients. The drug was well tolerated; however, GIT discomfort is a significant side effect that may necessitate drug withdrawal in some patients.
|How to cite this article:|
Al Saran K, Sabry A, Yehia A, Molhem A. Cinacalcet effect on severe hyperparathyroidism. Saudi J Kidney Dis Transpl 2010;21:867-71
|How to cite this URL:|
Al Saran K, Sabry A, Yehia A, Molhem A. Cinacalcet effect on severe hyperparathyroidism. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2020 Feb 28];21:867-71. Available from: http://www.sjkdt.org/text.asp?2010/21/5/867/68882
| Introduction|| |
Parathyroid hormone (PTH) plays a pivotal role in maintaining circulating levels of ionized calcium (Ca 2+ ) within a narrow physiological range.  Progressive kidney dysfunction results in hyperphosphatemia, calcitriol deficiency, and hypocalcemia. These abnormalities directly increase PTH levels via different mechanisms. 
Secondary hyperparathyroidism (SHPT) is a major complication of ESRD.  Excessive serum levels of iPTH are known to cause highturnover bone disease, i.e. osteitis fibrosa and have also been reported to increase the mortality risk in patients undergoing hemodialysis (HD). 
The traditional therapeutic approach for managing SHPT includes administration of vitamin D sterols and phosphate binders. However, treatment with vitamin D sterols may lead to hypercalcemia, hyperphosphatemia and elevations in the calcium-phosphorus product (Ca Χ PO4), which are associated with soft-tissue and cardiovascular calcification and increased mortality and morbidity, , and stringent targets for these parameters are recommended. 
The calcium-sensing receptor located on the surface of chief cells in the parathyroid gland is the principal regulator of PTH secretion and an ideal target for therapies to treat SHPT. , Calcimimetics such as cinacalcet are positive allosteric modulators of the calcium-sensing receptor that increase its sensitivity by lowering the threshold for activation by extracellular calcium ions. 
The aim of this study is to determine the efficacy and side effects of cinacalcet in the treatment of SHPT in HD patients.
| Subjects and Methods|| |
We prospectively studied the effect of cinacalcet 20 chronic HD patients (13 males, 7 females) regularly followed up at Prince Salman Center for Kidney Disease, Riyadh, Saudi Arabia, over 4 months. Mean HD duration was 29.13 ± 18.27 months.
Nine (60%) patients were on alpha-calcidol (mean dose 7.33 ± 3.39 μg/week) and the rest maintained elevated calcium and phosphorus during the study period. The starting dose of cinacalcet was 30 mg single oral daily dose, which was adjusted according to the PTH levels up to a maximum dose of 120 mg single oral daily dose (mean 64 ± 31.8 mg/day).
Serum PTH, Ca, phosphorous levels were measured before and at the end of the study and the effect of cinacalcet on PTH level was analyzed.
Weekly serum Ca and phosphorous levels were monitored for the first month of the study period then every two weeks. In case of severe hypocalcemia, the dose of cinacalcet was decreased or even withheld.
| Statistical Analysis|| |
All data were analyzed using the SPSS for windows software package release  . Data are presented as the mean and standard deviation. Student "t" test was applied as appropriate. P value of < 0.05 was considered significant.
| Results|| |
Out of 20 patients included in our study, 5 (20%) patients dropped out; 2 due to severe GIT discomfort, one to severe myalgia and arthralgia, one patient due to noncompliance and one died at home due to cardiac arrest. The remaining 15 patients (10 males, 5 females) with a mean age of 40 ± 12.86 years completed the study.
The original renal disease in the 15 study patients included diabetic nephropathy in 3 patients, hypertensive nephropathy in 3, chronic allograft nephropathy in 2, obstructive uropathy in 1, and unknown etiology in 6.
There was a significant decrease in the serum PTH levels 16 weeks of treatment with cinacalcet compared to that at the start (93.3 ± 25.6 pmol/L versus 46.4 ± 4.7 pmol/L) (target 15.831.6 pmol/L) (P< 0.000), the target PTH level (< 31.6 pmol/L) was achieved in 8 (53%) patients.
No significant changes were observed regarding serum calcium (2.05 mmol/L ± 0.14 mmol/ L versus 2.06 mmol/L ± 0.23 mmol/L) (normal: 2.12-2.52 mmol/L) and phosphorous (1.75 mmol/L ± 0.52 mmol/L versus 1.69 mmol/L ±0.37 mmol/L) (normal: 0.81 - 1.58 mmol/L) levels before and at the end of the study, respectively [Table 1].
|Table 1 :Clinical and biochemical data of the study patients pre and post cinacalcet therapy.|
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No significant changes were observed regarding Kt/V, hemoglobin levels, and Ca Χ PO4 product [Table 2].
| Discussion|| |
Hypercalcemia and hyperphosphatemia associated with traditional therapy for SHPT with vitamin D frequently necessitate treatment interruptions and may result in inadequate control of PTH and disease progression. ,,,, Because cinacalcet is not associated with such elevations in calcium and phosphorus, it may allow better achievement of the targets of therapy and possibly reduce complications associated with SHPT. 
The efficacy and safety profile of cinacalcet in our study was similar to those reported on HD patients from the United States and European countries,  Japan  and Spain.  Moreover, there are several reports indicating efficacy of cinacalcet after kidney transplantation. ,,
The dose range of cinacalcet in our study was lower than that used in the United States and European studies. The maximum dose in the United States and European studies was 180 mg/day, while it was only 120 mg/day in our study. One plausible explanation for the higher potency of cinacalcet in the Saudi patients may be a difference in the pharmacokinetics among the different populations. Unfortunately, no data is available about the pharmacokinetics of cinacalcet in the Saudi population.
Treatment with cinacalcet was generally well tolerated. Episodes of nausea and vomiting occurred, but were generally transient and mild to moderate in severity. However, GIT upset was the main side effect necessitating drug withdrawal in two patients. Serum calcium levels below the normal range were rarely associated with symptoms of hypocalcemia and were readily managed by adjustment of the doses of calcium-containing phosphate binders, vitamin D sterols, or both.
Our study nonetheless had certain limitations. Although parathyroid hormone levels decreased, we did not assess the effect of these changes on bone histological features, bone mass, arterial and soft-tissue calcification, arterial stiffness and cardiovascular events in this clinical trial. Long-term studies will be required to address these skeletal and cardiovascular issues adequately. Nevertheless, the effectiveness of cinacalcet in lowering parathyroid hormone levels and its favorable effect on biochemical variables with minimal adverse effects represent noteworthy findings. The use of treatment strategies that include cinacalcet may make it possible to achieve the more stringent therapeutic guidelines now recommended for management of SHPT. 
We conclude that cinacalcet is an effective therapy to decrease serum PTH levels and allow favorable management of the serum calcium and phosphorus levels in HD patients. Generally the drug was well tolerated; however GIT discomfort is a significant side effect that may necessitate drug withdrawal in some patients.
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Khalid Al Saran
Prince Salman Center for Kidney Disease, Riyadh
[Table 1], [Table 2]