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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2021  |  Volume : 32  |  Issue : 6  |  Page : 1628-1636
Cinacalcet for Severe Secondary Hyperparathyroidism in Children with End-stage Kidney Disease


1 Department of Pediatrics, Pediatric Nephrology Unit, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
2 Department of Pediatrics, Pediatric Nephrology Unit; Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
3 Department of Pediatrics, College of Medicine, King Saud University; Division of Pediatric Kidney Transplant, Organ Transplant Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
4 King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia

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Date of Web Publication27-Jul-2022
 

   Abstract 


Advanced chronic kidney disease with mineral and bone disorder have a significant obstacles to control serum bone profile [serum intact parathyroid hormone (iPTH), calcium and phosphorus] which subsequently have major effect on optimal bone strength, final adult height, and cardiovascular health. A retrospective, observational study, including a total of 36 children with end-stage kidney disease (ESKD). Fourteen children who were prescribed cinacalcet had been compared with the remaining 22 children who were managed with standard care. We report the efficacy and safety of cinacalcet for treatment of refractory secondary hyperparathyroidism (SHPT) in children with ESKD. After 6 months of cinacalcet treatment, the mean level of iPTH serum level decreased by 56% from 202 pmol/L [95% confidence interval (CI): 150-253] to 88 pmol/L (95% CI: 41-136), compared to the change observed in the control group (P <0.001). None of our patients reported serious adverse effects or developed hypocalcemia. Cinacalcet could be an effective and safe alternative to treat severe SHPT in children with ESKD. Further long-term and large-scale studies are necessary to confirm its safety and efficacy.

How to cite this article:
Sheerah AA, Al-Ahmed RA, El-Desoky SM, Alhasan KA, Albanna AS, Shalaby MA, Kari JA. Cinacalcet for Severe Secondary Hyperparathyroidism in Children with End-stage Kidney Disease. Saudi J Kidney Dis Transpl 2021;32:1628-36

How to cite this URL:
Sheerah AA, Al-Ahmed RA, El-Desoky SM, Alhasan KA, Albanna AS, Shalaby MA, Kari JA. Cinacalcet for Severe Secondary Hyperparathyroidism in Children with End-stage Kidney Disease. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 Aug 14];32:1628-36. Available from: https://www.sjkdt.org/text.asp?2021/32/6/1628/352423



   Introduction Top


Mineral and bone disorder (MBD) accompanies childhood chronic kidney disease (CKD) presents significant obstacles to optimal bone strength, final adult height, and cardiovascular health.[1] Childhood and adolescence are critical times for developing a healthy skeletal and vascular system. Alterations in bone or vascular biology in children affect the quality of life and lifespan.[2] In the early stages of CKD, serum calcium and phosphorus levels can be maintained within the normal range because of increasing parathyroid hormone (PTH) levels. However, as CKD progresses, compensatory mechanisms fail, resulting in hypocalcemia and hyperphosphatemia.[2]

Decreasing renal function induces phosphate retention and increases in fibroblast growth factor 23, which results in suppression of renal 1 alfa-hydroxylase activity, low circulating 1,25 dihydroxyvitamin D, decreased intestinal calcium absorption, increased serum PTH levels, and high-turnover renal osteodystrophy.[1]

Persistently elevated levels of PTH and progressive parathyroid gland hyperplasia characterize secondary hyperparathyroidism (SHPT). The elevated serum PTH, phosphorus (P), calcium (Ca), and calcium × phosphorus product (Ca×P) levels are also associated with vascular calcification, cardiovascular disease, and increased risk for mortality.[3] Patients are considered to have severe SHPT when serum P, Ca, Ca×P, and intact PTH (iPTH) levels can no longer be adequately controlled by conventional therapies.[4] The main parathyroid regulator is extracellular calcium; any increments in extracellular calcium are sensed by the calcium sensing receptors (CaSRs), which trigger a cascade of intracellular signaling that results in the inhibition of PTH synthesis and secretion.[5] PTH release in response to calcium takes place within seconds to minutes following signaling through the CaSRs.[6] Calcimimetics change the special configuration of CaSR and, as a result, CaSR sensitivity to calcium is increased.

In addition, experimental studies have shown that calcimimetics upregulate CaSRs and vitamin D receptors; thus, due to both properties, they may prevent or attenuate parathyroid hyperplasia.[7] Cinacalcet hydrochloride, a first-in-class calcimimetic, approved in both the United States and European Union, offers a new therapeutic approach to the treatment of SHPT.[8] Clinical trials involving SHPT patients have shown that cinacalcet efficiently lowers PTH levels and has the beneficial effect of reducing Ca and P serum levels in parallel.[9] In adult patients with end-stage kidney disease (ESKD), cinacalcet reduces the need for parathyroidectomy.[10],[11] In patients with ESKD receiving dialysis and suffering from SHPT, the Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guideline for CKD-MBD suggests the use of calcimimetics.[12] Recently, the European Medicines Agency approved the use of cinacalcet for the treatment of SHPT in children older than three years on dialysis for whom SHPT is not adequately controlled with standard therapy.[13],[14]


   Subjects and Methods Top


This study was conducted at two pediatric nephrology centers in the Kingdom of Saudi Arabia (pediatric nephrology center of excellence, King Abdulaziz University Hospital, Jeddah, and pediatric nephrology unit, King Khalid University Hospital, Riyadh).

It was a retrospective study of children with ESKD. We reported patients’ data over a 12- month period from January 2018 to December 2019. We included a total of 36 children (23 boys, 13 girls), aged one to 14 years, with stage 5 CKD and refractory SHPT. They were divided into two groups: 14 children were using cinacalcet and 22 were under conventional management of CKD-MBD according to KDIGO guidelines.[12] Twenty-four patients were on PD and nine on HD, and three children had not started yet on renal replacement therapy (RRT) as their parents refused dialysis [Table 1].{Table 1}

The Schwartz formula was used to calculate estimated glomerular filtration rate (eGFR).[15] Serum iPTH was measured with the Elecsys 2010 auto analyzer system (Roche Diagnostics, Basel, Switzerland). Seven pmol/L was considered the upper limit of normal iPTH. We divided them into two groups: children who were prescribed cinacalcet for uncontrolled severe SHPT and those who did not receive cinacalcet. Both groups were studied for a 12- month duration, with six months before and six months after commencing cinacalcet for the cinacalcet group. At time points before, at and following cinacalcet initiation, the means of all values collected within specified time intervals were the basis for retrospective data collection, including demographic information, analytic values of serum creatinine, iPTH, serum albumin, corrected serum Ca and P levels, Vitamin D3, and alkaline phosphatase.

The aim of this study was to assess the effectiveness and safety of cinacalcet for the treatment of SHPT in pediatric patients with advanced CKD on dialysis or under conservative management. The effectiveness was defined as a 30% or greater reduction in iPTH values from baseline over six months. Another effective outcome was the proportion of patients who achieved the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (NKF-KDOQI). In which it recommends targets for serum iPTH 150-300 pg/mL (15.9-31.8 pmol/L), serum phosphorus 3.5-5.5 mg/dL (1.13–1.78 mmol/L), total corrected serum calcium 8.4–9.5 mg/dL (2.102.37 mmol/L) and Ca×P <55 mg2/dL2 (<4.44 mmol2/L2).[12] According to our hospital protocol for the use of calcimimetics, in pediatric patients who have uncontrolled plasma levels of iPTH [defined as greater than 85 pmol/L (800 pg/mL)] that are refractory to standard therapy, and a normal or high adjusted serum calcium level; cinacalcet was not used or to be held in patients with hypocalcemia defined as Ca level <2.1 mmol/L, seizures, or liver function disorder. The dose was adjusted every four weeks according to iPTH and Ca levels.

The Ethics Research Committee at both centers granted permission to conduct the study. Consents from parents were waived as the study was retrospective and the collection of the data was anonymous.


   Statistical Analysis Top


For all analyses, we used STATA software (StataCorp LLC, 2011, release 12, College Station, TX). The proportion and mean for categorical and continuous variables, respectively, were used to describe patients’ demographic and disease characteristics. Outcome parameters are presented in bar charts. Comparative analysis was done using Student’s t-test. Paired t-test was used to compare the laboratory values at baseline and after six months of cinacalcet treatment in the different subgroups of patients stratified by dialysis method. Precision was determined using a 95% confidence interval (CI) and a P<0.05 was considered statistically significant.


   Results Top


Our study included 36 subjects out of which 14 received cinacalcet [9 on peritoneal dialysis (PD) and 4 on hemodialysis (HD), and one who did not start RRT] and 22 received conventional management of CKD-MBD (15 on PD, five on HD and two who were not started on RRT; control group). Table 1 showsthe patients’ baseline demographic and disease characteristics. The average dose of cinacalcet was 32 mg daily (SD = 8), 1.8 mg/kg/day (SD = 0.9).

The mean of iPTH serum levels decreased steadily: it dropped by 37.9% at three months and 56% after six months of treatment [from 202 pmol/L (95% CI: 150–253) to 88 pmol/L (95% CI: 41–136)], and it was statistically significant compared to the change of iPTH levels observed in the control group (P <0.001; [Figure 1]. The effect of cinacalcet treatment on iPTH was also statistically significant among patients undergoing either PD (P = 0.042) or HD (P = 0.007) when compared to pretreatment levels [Figure 2]. The use of cinacalcet was associated with a marginal reduction of phosphate serum levels (P = 0.072, Figure 3) when compared to changes among the control group. The effect on phosphate reduction was consistent regardless of the dialysis method, though it was statistically significant among the subset of patients undergoing PD (P<0.046; Figure 4).
Figure 1. Average change in iPTH serum levels during follow-up among cinacalcet and control groups.
PTH (Pmol/L): intact parathyroid hormone.


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Figure 2. The effect of cinacalcet on intact parathyroid hormone serum levels after 6 months of treatment among patients undergoing different dialysis methods.
HD: Hemodialysis, iPTH: intact parathyroid hormone, PD: Peritoneal dialysis.


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Figure 3. Average change of phosphate serum levels during follow-up among cinacalcet and control groups.
PO4: Phosphate (mmol/L).


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Figure 4. The effect of cinacalcet on phosphate serum levels after 6 months of treatment among patients undergoing different dialysis methods.
HD: Hemodialysis, PD: Peritoneal dialysis.


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There was no effect of cinacalcet on serum calcium levels (P = 0.381). None of our patients reported serious adverse effects or developed symptomatic hypocalcemia and there was no reported mortality.


   Discussion Top


Warady et al, recently in a prospective controlled trial, reported the efficacy and safety outcomes seen with cinacalcet in children with SHPT on dialysis.[16] Warady et al, in another study, reviewed all Amgen-sponsored cinacalcet pediatric trials and data from non-Amgen sponsored clinical studies and reported a variation in the effect of cinacalcet on PTH across studies.[14] Overall, 7.4% to 57.1% of children who received cinacalcet in an Amgen clinical trial attained PTH levels within recommended target ranges, and 22.2 to 70.6% observed a greater than or equal to 30% reduction in PTH. Similarly, significant reductions in PTH were demonstrated in all five non-Amgen-supported studies.[14] In our study, cinacalcet was effective in children with severe SHPT; iPTH was 37.9% reduced within the first three months and up to 56% reduced after six months of therapy, although none reached the NKF-K/DOQITM (KDOQITM) recommended targets for serum iPTH [150–300 pg/mL (15.9-31.8 pmol/L)]. This could be explained by the restricted maximum dose used (1.8 mg/kg/day), while in other studies the dose reached up to 2.5 mg/kg/d.[13] The maximum weight-adjusted daily dose within the Amgen-supported phase 2 and 3 studies ranged from 0.1 to 5.7 mg/kg/day.[14]

Cinacalcet can lead to a rapid decline in serum iPTH levels of greater than 50%, but it has not been proven whether cinacalcet can induce a reduction in parathyroid volume.[17]

Cinacalcet had comparable efficacy in HD and PD patients as well patients not on either mood regarding iPTH reduction, although we observed a reduction of phosphate with cinacalcet therapy, which was more pronounced in patients on PD. Several studies reported treatment with cinacalcet resulted in a significant decline in iPTH levels with no significant difference in serum calcium and phosphate levels, Ca×P,[18],[19],[20] while others reported significant improvement of all bone markers, including iPTH and phosphate levels.[21],[22]

Elevated serum phosphorus in the absence of dietary phosphate restriction or supplemental phosphate binders may contribute to cardiac-related causes of death through increased myocardial calcification and enhanced vascular calcification.[17] High plasma phosphate levels are independently correlated with increased mortality and morbidity. Serum phosphate levels above 5.6 mg/dL (=1.8 mmol/L) will increase the hazard ratio for mortality by 6% for everyone mg/dL (=0.3 mmol/L).[3] The risk of death increased 18% for each one mg/dL increment in serum phosphate.[11]

None of the patients in the treatment group were documented to have symptomatic hypocalcemia, as we did not find a significant difference in calcium levels between the treatment and control groups (P = 0.381; Figure 5). This could be explained by our restricted maximum dose of cinacalcet. Warady et al reported one fatal adverse event (fatal cardiopulmonary arrest) in one adolescent female patient on PD with a prolonged QT interval at baseline.[16] She was on 90 mg daily cinacalcet and her corrected serum calcium, which became available after fatality, was at a low level [5.3 mg/dL (1.325 mmol/L)]. In that study, the starting dose of cinacalcet was less than or equal to 0.20 mg/kg, with a maximum dose of 180 mg or 4.2 mg/kg, which was much higher in our cohort.
Figure 5. Average change of calcium serum levels during follow-up among cinacalcet and control groups.

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Recently, the European Society for Pediatric Nephrology and the CKD–MBD Working Group of the European Renal Association published a position statement for using cinacalcet in pediatric dialysis[13] in which they strongly recommend not starting cinacalcet in patients with albumin-corrected calcium levels <2.40 mmol/L; also, they strongly recommend not starting cinacalcet in patients with a prolonged QT interval. Hypocalcemia occurs in around 10% of cinacalcet-treated children,[14] usually during the first two weeks of treatment.[23]

In a study analyzing a large adult European HD population, 67% of cinacalcet-treated subjects were reported to have developed hypocalcemia, with 9% being severe, while it was mostly asymptomatic, transient, and not associated with an increase in cardiovascular events or deaths.[24]

Gastrointestinal adverse events (nausea and vomiting) are also most frequently associated with cinacalcet.[14] Episodes of nausea and vomiting are usually mild to moderate in severity and not a cause of medication withdrawal or dose reduction.[23] Affected patients could be managed with proton pump inhibitors and antiemetic medication. Cinacalcet is widely used by pediatric nephrologists in different parts of the world and the challenges faced are worth reporting.[25]

There were several limitations to this study, including the small sample size, being retrospective, and the short duration of followup.


   Conclusion Top


Cinacalcet could be an effective and safe alternative to treat severe SHPT in children with ESKD. Further long-term and large-scale studies are necessary to confirm its safety and efficacy.

Conflict of interest: None declared.



 
   References Top

1.
Wesseling-Perry K, Salusky IB. Chronic kidney disease: Mineral and bone disorder in children. Semin Nephrol 2013;33:169-79.  Back to cited text no. 1
    
2.
Moe S, Drüeke T, Cunningham J, et al. Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2006;69: 1945-53.  Back to cited text no. 2
    
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Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 2004;15:2208-18.  Back to cited text no. 3
    
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de Francisco AL. New strategies for the treatment of hyperparathyroidism incorporating calcimimetics. Expert Opin Pharmacother 2008;9:795-811.  Back to cited text no. 4
    
5.
Brown EM, Gamba G, Riccardi D, et al. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 1993;366:575-80.  Back to cited text no. 5
    
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Brown EM. Calcium receptor and regulation of parathyroid hormone secretion. Rev Endocr Metab Disord 2000;1:307-15.  Back to cited text no. 6
    
7.
Meola M, Petrucci I, Barsotti G. Long-term treatment with cinacalcet and conventional therapy reduces parathyroid hyperplasia in severe secondary hyperparathyroidism. Nephrol Dial Transplant 2009;24:982-9.  Back to cited text no. 7
    
8.
Torres PU. Cinacalcet HCl: A novel treatment for secondary hyperparathyroidism caused by chronic kidney disease. J Ren Nutr 2006; 16:253-8.  Back to cited text no. 8
    
9.
Kawata T, Tokunaga S, Murai M, et al. A novel calcimimetic agent, evocalcet (MT- 4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro. PLoS One 2018;13:e0195316.  Back to cited text no. 9
    
10.
Palmer SC, Nistor I, Craig JC, et al. Cinacalcet in patients with chronic kidney disease: A cumulative meta-analysis of randomized controlled trials. PLoS Med 2013;10: e1001436.  Back to cited text no. 10
    
11.
Ballinger AE, Palmer SC, Nistor I, Craig JC, Strippoli GF. Calcimimetics for secondary hyperparathyroidism in chronic kidney disease patients. Cochrane Database Syst Rev 2014;(12):CD006254.  Back to cited text no. 11
    
12.
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl 2017;7:1-59.  Back to cited text no. 12
    
13.
Bacchetta J, Schmitt CP, Ariceta G, et al. Cinacalcet use in paediatric dialysis: A position statement from the European Society for Paediatric Nephrology and the Chronic Kidney Disease-Mineral and Bone Disorders Working Group of the ERA-EDTA. Nephrol Dial Transplant 2020;35:47-64.  Back to cited text no. 13
    
14.
Warady BA, Ng E, Bloss L, Mo M, Schaefer F, Bacchetta J. Cinacalcet studies in pediatric subjects with secondary hyperparathyroidism receiving dialysis. Pediatr Nephrol 2020;35: 1679-97.  Back to cited text no. 14
    
15.
Schwartz GJ, Muñoz A, Schneider MF, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol 2009;20:629-37.  Back to cited text no. 15
    
16.
Warady BA, Iles JN, Ariceta G, et al. A randomized, double-blind, placebo-controlled study to assess the efficacy and safety of cinacalcet in pediatric patients with chronic kidney disease and secondary hyperparathyroidism receiving dialysis. Pediatr Nephrol 2019;34:475-86.  Back to cited text no. 16
    
17.
Platt C, Inward C, McGraw M, et al. Middle-term use of cinacalcet in paediatric dialysis patients. Pediatr Nephrol 2010;25:143-8.  Back to cited text no. 17
    
18.
Komaba H, Nakanishi S, Fujimori A, et al. Cinacalcet effectively reduces parathyroid hormone secretion and gland volume regardless of pretreatment gland size in patients with secondary hyperparathyroidism. Clin J Am Soc Nephrol 2010;5:2305-14.  Back to cited text no. 18
    
19.
Silverstein DM, Kher KK, Moudgil A, Khurana M, Wilcox J, Moylan K. Cinacalcet is efficacious in pediatric dialysis patients. Pediatr Nephrol 2008;23:1817-22.  Back to cited text no. 19
    
20.
Alharthi AA, Kamal NM, Abukhatwah MW, Sherief LM. Cinacalcet in pediatric and adolescent chronic kidney disease: A singlecenter experience. Medicine (Baltimore) 2015; 94:e401.  Back to cited text no. 20
    
21.
Joseph C, Shah S, Geer J, Juarez-Calderon M, Srivaths PR, Swartz SJ. Cinacalcet for secondary hyperparathyroidism in end-stage renal disease patients below age 5 years. Clin Nephrol 2019;92:279-86.  Back to cited text no. 21
    
22.
Muscheites J, Wigger M, Drueckler E, Fischer DC, Kundt G, Haffner D. Cinacalcet for secondary hyperparathyroidism in children with end-stage renal disease. Pediatr Nephrol 2008;23:1823-9.  Back to cited text no. 22
    
23.
Bover J, Ureña P, Ruiz-García C, et al. Clinical and practical use of calcimimetics in dialysis patients with secondary hyperparathyroidism. Clin J Am Soc Nephrol 2016;11:161-74.  Back to cited text no. 23
    
24.
Louie KS, Erhard C, Wheeler DC, Stenvinkel P, Fouqueray B, Floege J. Cinacalcet-induced hypocalcemia in a cohort of European haemodialysis patients: Predictors, therapeutic approaches and outcomes. J Nephrol 2020;33:803-16.  Back to cited text no. 24
    
25.
Al-Ahmad RA, Sheerah AA, Alhasan KA, Kari JA. Cinacalcet use in pediatric chronic kidney disease. A survey study. Saudi Med J 2020;41:479-84.  Back to cited text no. 25
    

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Correspondence Address:
Areej Adel Sheerah
Department of Pediatrics, Pediatric Nephrology Unit, King Abdulaziz University, P. O. Box 80215, Jeddah 21589, Saudi Arabia.
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1319-2442.352423

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