Pediatric Nephrology

, Volume 34, Issue 3, pp 413–422 | Cite as

Use of calcimimetics in children with normal kidney function

  • Judith Sebestyen VanSickle
  • Tarak Srivastava
  • Uri S. AlonEmail author
Educational Review


The calcium-sensing receptor (CaSR) plays an important role in the homeostasis of serum ionized calcium by regulating parathyroid hormone (PTH) secretion and tubular calcium handling. Calcimimetics, which act by allosteric modulation of the CaSR, mimic hypercalcemia resulting in suppression of PTH release and increase in calciuria. Mostly used in children to treat secondary hyperparathyroidism associated with advanced renal failure, we have shown that calcimimetics can also be successfully used in children with bone and mineral disorders in which elevated PTH plays a detrimental role in skeletal pathophysiology in the face of normal kidney function. The current review briefly discusses the role of the CaSR and calcimimetics in calcium homeostasis, and then addresses the potential applications of calcimimetics in children with normal kidney function with disorders in which suppression of PTH is beneficial.


Calcium-sensing receptor Calcimimetics Hyperparathyroidism Parathyroid hormone Rickets 


Compliance with ethical standards

Conflict of interests

The authors declare no conflict of interest.


  1. 1.
    Portale AA, Perwad F (2016) Calcium and phosphorous. In: Avner E, Niaudet P, Emma F, Harmon WE, Yoshikawa N, Goldstein SL (eds) Pediatric nephrology, 7th edn. Springer, New York, pp 231–266Google Scholar
  2. 2.
    Gardella TJ, Juppner H, Brown EM, Kronenberg HM, Potts Jr JT (2010) Parathyroid hormone and parathyroid hormone-related peptide in the regulation of calcium homeostasis and bone development. In: DeGroot LJ, Jameson JL (eds) Endocrinology, 6th edn. W.B. Saunders, Philadelphia, pp 1040–1073Google Scholar
  3. 3.
    Hebert SC (1996) Extracellular calcium-sensing receptor: implications for calcium and magnesium handling in the kidney. Kidney Int 6:2129–2139CrossRefGoogle Scholar
  4. 4.
    Brown EM (1999) Physiology and pathophysiology of the extracellular calcium-sensing receptor. Am J Med 2:238–253CrossRefGoogle Scholar
  5. 5.
    Miyamoto K, Ito M, Tatsumi S, Kuwahata M, Segawa H (2007) New aspect of renal phosphate reabsorption: the type IIc sodium-dependent phosphate transporter. Am J Nephrol 5:503–515CrossRefGoogle Scholar
  6. 6.
    Daniela R, Brown EM (2010) Physiology and pathophysiology of the calcium-sensing receptor in the kidney. Am J Physiol Ren Physiol 298:485–499CrossRefGoogle Scholar
  7. 7.
    McKay CP, Portale A (2008) Emerging topics in pediatric. Bone and mineral disorders. Semin Nephrol 4:370–378Google Scholar
  8. 8.
    Hammerland LG, Garrett JE, Hung BC, Levinthal C, Nemeth EF (1998) Allosteric activation of the Ca2+ receptor expressed in Xenopus laevis oocytes by NPS 467 or NPS 568. Mol Pharmacol 53:1083–1088PubMedGoogle Scholar
  9. 9.
    Riccardi D, Valenti G (2016) Localization and function of the renal calcium-sensing receptor. Nat Rev Nephrol 12:414–425CrossRefGoogle Scholar
  10. 10.
    Alfadda TI, Saleh AM, Houillier P, Geibel JP (2014) Calcium-sensing receptor 20 years later. Am J Physiol Cell Physiol 307:C221–C231CrossRefGoogle Scholar
  11. 11.
    Brown EM, MacLeod RJ (2001) Extracellular calcium sensing and extracellular calcium signaling. Physiol Rev 81:239–297CrossRefGoogle Scholar
  12. 12.
    Auron A, Alon US (2017) Hypercalcemia: a consultant’s approach. Pediatr Nephrol.
  13. 13.
    Zhang L, Ji T, Wang Q, Meng K, Zhang R, Yang H, Liao C, Ma L, Jiao J (2017) Calcium-sensing receptor stimulation in cultured glomerular podocytes induces TRPC6-dependent calcium entry and RhoA activation. Cell Physiol Biochem 43:1777–1789CrossRefGoogle Scholar
  14. 14.
    Oh J, Beckmann J, Bloch J, Hettgen V, Mueller J, Li L, Hoemme M, Gross ML, Penzel R, Mundel P, Schaefer F, Schmitt CP (2011) Stimulation of the calcium-sensing receptor stabilizes the podocyte cytoskeleton, improves cell survival, and reduces toxin-induced glomerulosclerosis. Kidney Int 80:483–492CrossRefGoogle Scholar
  15. 15.
    Abdel-Magid AF (2015) Allosteric modulators: an emerging concept in drug discovery. ACS Med Chem Lett 6:104–107CrossRefGoogle Scholar
  16. 16.
    Wesseling-Perry KJ, Salusky IB (2013) Phosphate binders, vitamin D and calcimimetics in the management of chronic kidney disease-mineral bone disorders (CKD-MBD) in children. Pediatr Nephrol 28:617–625CrossRefGoogle Scholar
  17. 17.
    Goodman WG (2003) Calcimimetic agents and secondary hyperparathyroidism: rationale for use and results from clinical trials. Pediatr Nephrol 18:1206–1210CrossRefGoogle Scholar
  18. 18.
    Alharthi AA, Naglaa MK, Abukhatwah WM, Sherief LM (2015) Cinacalcet in pediatric and adolescent chronic kidney disease: a single-center experience. Medicine 94:e401CrossRefGoogle Scholar
  19. 19.
    Chonchol M, Locatelli F, Abboud HE, Charytan C, de Francisco ALM, Jolly S, Kaplan M, Roger SD, Sarkar S, Albizem MB, Mix TC, Kubo Y, Block GA (2009) A randomized, double-blind, placebo-controlled study to assess the efficacy and safety of cinacalcet HCl in participants with CKD not receiving dialysis. Am J Kidney Dis 53:197–207Google Scholar
  20. 20.
    Pérez-Ricart A, Galicia-Basart M, Alcalde-Rodrigo M, Segarra-Medrano A, Suñé-Negre JM, Montoro-Ronsano JB (2016) Effectiveness of cinacalcet in patients with chronic kidney disease and secondary hyperparathyroidism not receiving dialysis. PLoS One 11(9):e0161527CrossRefGoogle Scholar
  21. 21.
    Wang W, Konk J, Nie M, Jiang Y, Me L (2017) Primary hyperparathyroidism in Chinese children and adolescents: a single-center experience at Peking Union Medical College Hospital. Clin Endocrinol 87:865–873CrossRefGoogle Scholar
  22. 22.
    Shoback DM, Bilezikian JP, Turner SA, McCary LC, Guo MD, Peacock M (2003) The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism. J Clin Endocinol Metab 88:5644–5649CrossRefGoogle Scholar
  23. 23.
    Peacock M, Bilezikian JP, Klassen PS, Gou MD, Turner SA, Shoback D (2005) Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 90:135–141CrossRefGoogle Scholar
  24. 24.
    Mittendorf EA, McHenry CR (2005) Parathyroid carcinoma. J Surg Oncol 89:136–142CrossRefGoogle Scholar
  25. 25.
    Sloand JA, Shelly MA (2006) Normalization of lithium-induced hypercalcemia and hyperparathyroidism with cinacalcet hydrochloride. Am J Kidney Dis 48:832–837CrossRefGoogle Scholar
  26. 26.
    Pollak MR, Brown EM, Chou YH, Herbert SC, Marx SJ, Steinmann B, Levi T, Seidman CE, Seidman JG (1993) Mutation in the human Ca2+-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 75:1297–1303CrossRefGoogle Scholar
  27. 27.
    Festen-Spanjer B, Haring CM, Koster JB, Mudde AH (2007) Correction of hypercalcaemia by cinacalcet in familial hypocalciuric hypercalcaemia. Clin Endocrinol 68:324–325Google Scholar
  28. 28.
    Sethi BK, Nagesh VS, Kelwade J, Parekh H, Dukle V (2017) Utility of cinacalcet in familial hypocalciuric hypercalcemia. Indian J Endocrinol Metab 21:362–363CrossRefGoogle Scholar
  29. 29.
    Alon US, VanDeVoorde RG (2010) Beneficial effect of cinacalcet in a child with familial hypocalciuric hypercalcemia. Pediatr Nephrol 25:1747–1750CrossRefGoogle Scholar
  30. 30.
    Izzi B, Van Geet C, Freson K (2012) Recent advances in GNAS epigenetic research of pseudohypoparathyroidism. Curr Mol Med 12:566–573CrossRefGoogle Scholar
  31. 31.
    Farfel Z (1999) Pseudohypohyperparathyroidism-pseudohypoparathyroidism type Ib. J Bone Miner Res 14:1016CrossRefGoogle Scholar
  32. 32.
    Srivastava T, Krudys J, Mardis NJ, Sebestyen-VanSickle J, Alon US (2016) Cinacalcet as adjunctive therapy in pseudohypoparathyroidism type 1b. Pediatr Nephrol 31:795–800CrossRefGoogle Scholar
  33. 33.
    Tiosano D, Hochberg Z (2009) Hypophosphatemia: the common denominator of all rickets. J Bone Miner Metab 27:392–401CrossRefGoogle Scholar
  34. 34.
    Malloy PJ, Feldman D (2010) Genetic disorders and defects in vitamin D action. Endocrinol Metab Clin N Am 39:333–346CrossRefGoogle Scholar
  35. 35.
    Weisman Y, Bab I, Gazit D, Spirer Z, Jaffe M, Hochberg Z (1987) Long-term intracaval calcium infusion therapy in end-organ resistance to 1,25-dihydroxyvitamin D. Am J Med 83:984–990CrossRefGoogle Scholar
  36. 36.
    Srivastava T, Alon US (2013) Cinacalcet as adjunctive therapy for hereditary 1,25-dihydroxyvitamin D-resistant rickets. J Bone Miner Res 28:992–996CrossRefGoogle Scholar
  37. 37.
    Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL (2011) A clinician’s guide to X-linked hypophosphatemia. J Bone Miner Metab 26:1381–1388CrossRefGoogle Scholar
  38. 38.
    Penido M, Alon US (2014) Hypophosphatemic rickets due to perturbations in renal tubular function. Pediatr Nephrol 29:361–373CrossRefGoogle Scholar
  39. 39.
    Alon US (2011) Fibroblast growth factor (FGF)-23: a new hormone. European J Pediatr 170:545–554Google Scholar
  40. 40.
    Rasmussen H, Pechet M, Anast C, Mazur A, Gertner J, Broadus AE (1981) Long-term treatment of familial hypophosphatemic rickets with oral phosphate and 1 α-hydroxyvitaminD3. J Peidatr 99:16–25CrossRefGoogle Scholar
  41. 41.
    Harrell RM, Lyles KW, Harrelson JM, Friedman NE, Drezner MK (1985) Healing of bone disease in X-linked hypophosphatemic rickets/osteomalacia. J Clin Invest 75:1858–1868CrossRefGoogle Scholar
  42. 42.
    Raeder H, Shaw N, Netelenbos C, Bjerknes R (2008) A case of X-linked hypophosphatemic rickets: complications and the therapeutic use of cinacalcet. Euro J Endocrinol 159:S101–S105CrossRefGoogle Scholar
  43. 43.
    Yavropoulo MP, Kosta K, Gotzamani Psarrakou A, Papazisi A, Tranga T, Ventis S, Yovos JG (2010) Cinacalcet in hyperparathyroidism secondary to X-linked hypophosphatemic rickets: case report and brief literature review. Hormones 9:274–278CrossRefGoogle Scholar
  44. 44.
    Alon US, Levy-Olomucki L, Wayne V, Moore JS, Liu S, Quarles DL (2008) Calcimimetics as an adjuvant treatment for familial Hypophosphatemic rickets. Clin J Am Soc Nephro 3:658–664CrossRefGoogle Scholar
  45. 45.
    Alon US, Chan JCM (1984) Effects of PTH and 1,25 dihydroxyvitamin D3 on tubular handling of phosphate in hypophosphatemic rickets. J Clin Endocrinol Metab 58:671–675CrossRefGoogle Scholar
  46. 46.
    Alon US, Jarka D, Monachino PJ, Sebestyen VanSickle J, Srivastava T (2017) Cinacalcet as an alternative to phosphate therapy in X-linked hypophosphatemic rickets. Clin Endocrinol 87:114–116CrossRefGoogle Scholar
  47. 47.
    Hufnagle KG, Khan SN, Penn D, Cacciarelli A, Williams P (1982) Renal calcification: a complication of long-term furosemide in preterm infants. Pediatrics 70:360–363PubMedGoogle Scholar
  48. 48.
    Saarela T, Lanning P, Koivisto M, Paavilainen T (1999) Nephrocalcinosis in full-term infants receiving furosemide treatment for congestive heart failure: a study of the incidence and 2-year follow up. Eur J Pediatr 158:668–672CrossRefGoogle Scholar
  49. 49.
    Venkataraman PS, Han BF, Tsang RC, Daugherty CC (1983) Secondary hyperparathyroidism and bone disease in infants receiving long-term furosemide therapy. Am J Dis Child 137:1157–1161PubMedGoogle Scholar
  50. 50.
    Corapi K, McMahon GM, Wenger J, Seifter J, Bhan I (2015) Association of loop diuretic use with higher parathyroid hormone levels in patients with normal renal function. JAMA Intern Med 175:137–138CrossRefGoogle Scholar
  51. 51.
    Coe FL, Canterbury JM, Firpo JJ, Reiss E (1973) Evidence for secondary hyperparathyroidism in idiopathic hypercalciuria. J Clin Invest:134–142Google Scholar
  52. 52.
    Fujita T, Delea CS, Bartter FC (1985) The effects of oral furosemide on the response of urinary excretion of cyclic adenosine monophosphate and phosphate to parathyroid extract in normal subjects. Nephron 41:333–336CrossRefGoogle Scholar
  53. 53.
    Alon US, Nichols MA, Alon MM (1996) Critical role of parathyroid hormone in furosemide-induced nephrocalcinosis in the young rat. Pediatr Res 39:357AGoogle Scholar
  54. 54.
    Pattaragarn A, Fox J, Alon US (2004) Effect of the calcimimetic NPS R-467 on furosemide-induced nephrocalcinosis in the young rat. Kidney Int 65:1684–1689CrossRefGoogle Scholar
  55. 55.
    Srivastava T, Jafri S, Truog W, Sebestyen VanSickle J, Maimtim W, Alon US (2017) Successful reversal of furosemide-induced secondary hyperparathyroidism with cinacalcet. Pediatrics 140:e20163781CrossRefGoogle Scholar
  56. 56.
    Najak ZD, Harris EM, Jr LA, Pruitt AW (1983) Pulmonary effects of furosemide in preterm infants with lung disease. J Pediatr 102:758–763CrossRefGoogle Scholar
  57. 57.
    Muller ME, Forni-Ogna V, Maillard M, Stoudmann C, Zweiacker C, Anex C, Wuerzner G, Burnier M, Bonny O (2015) Furosemide stimulation of parathormone in humans: role of the calcium-sensing receptor and the renin-angiotensin system. Pflugers Arch 467:2413–2421Google Scholar
  58. 58.
    Srivastava T, Alon US (2007) Pathophysiology of hypercalciuria in children. Pediatr Nephrol (10):1659–1673Google Scholar
  59. 59.
    Leppla D, Browne R, Hill K, Pak CY (1983) Effect of amiloride with or without hydrochlorothiazide on urinary calcium and saturation of calcium salts. J Clin Endocrinol Metab 57:920–924CrossRefGoogle Scholar

Copyright information

© IPNA 2018

Authors and Affiliations

  • Judith Sebestyen VanSickle
    • 1
  • Tarak Srivastava
    • 1
    • 2
  • Uri S. Alon
    • 1
    Email author
  1. 1.Bone and Mineral Disorders Clinic, Division of Nephrology, Children’s Mercy HospitalUniversity of Missouri at Kansas CityKansas CityUSA
  2. 2.Renal Research Laboratory, Research and DevelopmentKansas City VA Medical CenterKansas CityUSA

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