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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2010  |  Volume : 21  |  Issue : 5  |  Page : 867-871
Cinacalcet effect on severe hyperparathyroidism


1 Prince Salman Center for Kidney Disease, Riyadh, Saudi Arabia
2 Mansoura Urology and Nephrology Center, Mansoura University, Egypt

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Date of Web Publication31-Aug-2010
 

   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 2019 Dec 8];21:867-71. Available from: http://www.sjkdt.org/text.asp?2010/21/5/867/68882

   Introduction Top


Parathyroid hormone (PTH) plays a pivotal role in maintaining circulating levels of ionized calcium (Ca 2+ ) within a narrow physiological range. [1] Progressive kidney dysfunction results in hyperphosphatemia, calcitriol deficiency, and hypocalcemia. These abnormalities directly in­crease PTH levels via different mechanisms. [2]

Secondary hyperparathyroidism (SHPT) is a major complication of ESRD. [3] 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). [4]

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, [5],[6] and stringent targets for these parameters are recommended. [7]

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. [8],[9] 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. [10]

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 Top


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 Top


All data were analyzed using the SPSS for windows software package release [16] . 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 Top


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].
Table 2 :Biochemical measures before and after the study.

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   Discussion Top


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. [11],[12],[13],[14],[15] 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. [16]

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, [17] Japan [18] and Spain. [19] Moreover, there are several reports indicating efficacy of cinacalcet after kidney transplantation. [20],[21],[22]

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. [7]

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.

 
   References Top

1.Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol 2005;289:F8­F28.  Back to cited text no. 1      
2.Pitts TO, Piraino BH, Mitro R, et al. Hyper­parathyroidism and 1,25-dihydroxyvitamin D deficiency in mild, moderate, and severe renal failure. J Clin Endocrinol Metab 1988;67:876.  Back to cited text no. 2      
3.Slatopolsky E, Brown A, Dusso A. Pathogene­sis of secondary hyperparathyroidism. Kidney Int 1999;56(Suppl 73):S14-9.  Back to cited text no. 3      
4.Young EW, Albert JM, Satayathum S, et al. Predictors and consequences of altered mineral metabolism:the dialysis outcomes and practice patterns study. Kidney Int 2005;67:1179-87.  Back to cited text no. 4      
5.Ganesh SK, Stack AG, Levin NW, Hulbert­Shearon T, Port FK. Association of elevated serum PO4, Ca x PO4 product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol 2001;12:2131-8.  Back to cited text no. 5      
6.Johnson CA, McCarthy J, Bailie GR, Deane J, Smith S. Analysis of renal bone disease treatment in dialysis patients. Am J Kidney Dis 2002;39:1270-7.  Back to cited text no. 6      
7.National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003;42:S1-202.  Back to cited text no. 7      
8.Nemeth EF, Steffey ME, Hammerland LG, et al. Calcimimetics with potent and selective activity on the parathyroid calcium receptor. Proc Natl Acad Sci USA 1998;95:4040-5.  Back to cited text no. 8      
9.Nemeth EF, Heaton WH, Miller M, et al. Pharmacodynamics of the type II calcimimetic compound cinacalcet HCl. J Pharmacol Exp Ther 2004;308:627-35.  Back to cited text no. 9      
10.Hammerland LG, Garrett JE, Hung BC, Levinthal C, Nemeth EF. Allosteric activation of the Ca2+ receptor expressed in Xenopus laevis oocytes by NPS 467 or NPS 568. Mol Pharmacol 1998;53:1083-8.  Back to cited text no. 10      
11.Maung HM, Elangovan L, Frazao JM, et al. Efficacy and side effects of intermittent intra­venous and oral doxercalciferol (1 -hydroxy­vitamin D2) in dialysis patients with secondary hyperparathyroidism:A sequential comparison. Am J Kidney Dis 2001;37:532-43.  Back to cited text no. 11      
12.Goodman WG. Recent developments in the management of secondary hyperparathyroidism. Kidney Int 2001;59:1187-201.  Back to cited text no. 12      
13.Locatelli F, Cannata-Andia J, Drueke T, et al. Management of disturbances of calcium and phosphate metabolism in chronic renal insuf­ficiency, with emphasis on the control of hyperphosphataemia. Nephrol Dial Transplant 2002;17:723-1.  Back to cited text no. 13      
14.Ganesh SK, Stack AG, Levin NW, Hulbert­Shearon T, Port FK. Association of elevated serum PO4, Ca Χ PO4 product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol 2001; 12:2131-8.  Back to cited text no. 14      
15.Raggi P, Boulay A, Chasan-Taber S, Amin N, Dillon M, Burke SK, Chertow GM. Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and car­diovascular disease?.J Am Coll Cardiol. 2002; 39(4):695-701.  Back to cited text no. 15      
16.Lindberg JS, Culleton B, Wong G, et al. Cinacalcet HCl, an oral calcimimetic agent for the treatment of secondary hyperparathyroi­dism in hemodialysis and peritoneal dialysis: A randomized, double-blind, multicenter study. J Am Soc Nephrol 2005;16:800-7.  Back to cited text no. 16      
17.Block GA, Martin KJ, de Francisco AL, et al. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 2004;350:1516-25.  Back to cited text no. 17      
18.Fukagawa M, Yumita S, Akizawa T, et al. Cinacalcet (KRN1493) effectively decreases the serum intact PTH level with favourable control of the serum phosphorus and calcium levels in Japanese dialysis patients. Nephrol Dial Transplant 2008;23(1):328-35.  Back to cited text no. 18      
19.Arenas M, Alvarez-Ude F, Gill M, et al. Imple­mentation of 'K/DOQI clinical practice guide-lines for bone metabolism and disease in chronic kidney disease' after the introduction of cina­calcet in a population of patients on chronic haemodialysis. Nephrol Dial Transplant 2007; 22:1-6.  Back to cited text no. 19      
20.Kruse AE, Eisenberger U, Frey FJ, et al. The calcimimetic cinacalcet normalizes serum calc­ium in renal transplant patients with persistent hyperparathyroidism. Nephrol Dial Transplant 2005;20:1311-4.  Back to cited text no. 20      
21.Serra AL, Schwarz AA, Wick FH, et al. Suc­cessful treatment of hypercalcemia with cina­calcet in renal transplant recipients with persistent hyperparathyroidism. Nephrol Dial Transplant 2005;20:1315-9.  Back to cited text no. 21      
22.Apostolou T, Damianou L, Kotsiev V, et al. Treatment of severe hypercalcemia due to re­fractory hyperparathyroidism in renal trans­plant patients with the calcimimetic agent cina­calcet. Clin Nephrol 2006;65:374-7.  Back to cited text no. 22      

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Correspondence Address:
Khalid Al Saran
Prince Salman Center for Kidney Disease, Riyadh
Saudi Arabia
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PMID: 20814122

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    Abstract
    Introduction
    Subjects and Methods
    Statistical Analysis
    Results
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    References
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