ЗНАЧИМОСТЬ ЦИНАКАЛЬЦЕТА В КОРРЕКЦИИ НАРУШЕНИЙ ФОСФОРНО-КАЛЬЦИЕВОГО БАЛАНСА У БОЛЬНЫХ С ХРОНИЧЕСКОЙ БОЛЕЗНЬЮ ПОЧЕК

Вторичный гиперпаратиреоз (ВГПТ) является частым проявлением хронической болезни почек (ХБП) и приводит не только к остеодистрофии, увеличивающей риск переломов, но и к внекостным проявлениям, включающим сосудистую кальцификацию, гипертензию, анемию, кожный зуд и сексуальные расстройства. Эпидемиологические данные указывают на связь высоких значений паратгормона (ПТГ), кальция (Са) и фосфата (Р) крови с повышенной смертностью пациентов. Традиционная терапия ВГПТ у пациентов на заместительной почечной терапии витамином D и фосфат-связывающими препаратами подавляет секрецию паратгормона (ПТГ), но при этом вызывает гиперкальциемию и гиперфосфатемию, способствующих развитию эктопической кальцификации и повышению летальности. Поэтому в 2004 г. в клиническую практику для коррекции ВГПТ был введен новый класс препаратов – кальцимиметиков (КМ), единственным представителем которых на сегодняшний день является цинакальцет (ЦК)(Mimpara, Sensipar). ЦК повышает порог реагирования кальций-чувствительных рецепторов паращитовидных желез на кальций крови – наиболее сильный ингибитор секреции ПТГ, что приводит к снижению уровня в крови этого гормона, уменьшению резорбции Са и Р из костей и падению их концентраций в крови. В ряде исследований было показано, что КМ способны вызывать регрессию гиперплазии ПЩЖ, снижая риск выполнения паратиреоидэктомии. Получены доказательства, что ЦК уменьшает тяжесть уремической остеодистрофии и частоты переломов. Благодаря снижению уровней ПТГ, Са и Р крови, а также прямому действию на сосуды ЦК тормозит развитие сосудистого кальциноза. В экспериментальных исследованиях показано, что ЦК уменьшает выраженности артериальной гипертензии, вероятно, вследствие прямого вазодилатирующего эффекта, а также подавления секреции ренина. В конечном итоге применение ЦК снижает частоту госпитализаций по поводу кардиоваскулярной патологии. В настоящее время проводится исследование влияния терапии ЦК на выживаемость пациентов. Препарат надежно контролирует ВГПТ у пациентов после трансплантации почки и позволяет избежать выполнения паратиреоидэктомии. В опытах на животных с применением кальцимиметиков получены данные об эффективном снижении выраженности протеинурии и замедлении прогрессирования снижения скорости клубочковой фильтрации, что обосновывает применение ЦК на ранних стадиях ХБП, но эти данные требуют клинического подтверждения. Увеличивается доказательная база эффективности комбинации ЦК и малых доз ВД у пациентов на заместительной почечной терапии (принимая во внимание позитивные кардио- и нефропротективные эффекты последнего).

1. Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 1998; 31(4):607-617

2. Ganesh SK, Stack AG, Levin NW et al. Association of elevated serum PO(4), Ca x PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol 2001;12(10):2131-2138

3. Gutierrez OM, Mannstadt M, Isakova T et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008;359(6):584-592

4. Negri AL. Association of oral calcitriol with improved survival in non-dialysed and dialysed patients with CKD. Nephrol Dial Transplant 2009;24(2):341-344

5. Teng M, Wolf M, Lowrie E et al. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 2003;349(5):446-456

6. Shoji T, Shinohara K, Kimoto E et al. Lower risk for cardiovascular mortality in oral 1alpha-hydroxy vitamin D3 users in a haemodialysis population. Nephrol Dial Transplant 2004; 19(1):179-184

7. Kovesdy CP, Ahmadzadeh S, Anderson JE, Kalantar-Zadeh K. Association of activated vitamin D treatment and mortality in chronic kidney disease. Arch Intern Med 2008; 168(4):397-403

8. Blacher J, Guerin AP, Pannier B et al. Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 2001;38(4):938-942

9. Goodman WG, Goldin J, Kuizon BD et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000;342(20):1478-1483

10. Proudfoot D, Shanahan CM. Biology of calcification in vascular cells: intima versus media. Herz 2001;26(4):245-251

11. Edmonds ME. Medial arterial calcification and diabetes mellitus. Z Kardiol 2000;89 Suppl 2:101-104

12. London GM, Drueke TB. Atherosclerosis and arteriosclerosis in chronic renal failure. Kidney Int 1997; 51(6): 1678-1695

13. Diehm C, Kareem S, Lawall H. Epidemiology of peripheral arterial disease. Vasa 2004;33(4):183-189

14. Guerin AP, London GM, Marchais SJ, Metivier F. Arterial stiffening and vascular calcification in end-stage renal disease. Nephr Dial Transpl 2000;15:1014-1021

15. Bro S, Olgaard K. Effects of excess PTH on nonclassical target organs. Am J Kidney Dis 1997;30(5):606-620

16. Cunningham J. Are parathyroidectomies still appropriate in chronic dialysis patients? Semin Dial 2000; 13(5): 275-278

17. Hruska KA, Saab G, Mathew S, Lund R. Renal osteodystrophy, phosphate homeostasis, and vascular calcification. Semin Dial 2007;20(4):309-315

18. Levin A, Bakris GL, Molitch M et al. Prevalence of abnormal serum vitamin D, PTH, Calcium, and phosphorua in patients with chronic kidney disease: Results of the study to evaluate early kidney disease. Kidney Int 2007;71:31-38

19. Wang Y, Sun Z. Current understanding of klotho. Ageing Res Rev 2008 Oct 31 [Epub ahead of print]

20. Torres PU, Prie D, Beck L et al. Klotho gene, phosphocalcic metabolism, and survival in dialysis. J Ren Nutr 2009;19(1):50-56

21. Wetmore JB, Quarles LD. Calcimimetics or vitamin D analogs for suppressing parathyroid hormone in end-stage renal disease: time for a paradigm shift? Nat Clin Pract Nephrol 2009;5(1):24-33

22. Urakawa I, Yamazaki Y, Shimada T et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006;444(7120):770-774

23. Kuro-o M, Matsumura Y, Aizawa H et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997;390(6655):45-51

24. Koh N, Fujimori T, Nishiguchi S et al. Severely reduced production of klotho in human chronic renal failure kidney. Biochem Biophys Res Commun 2001;280(4):1015-1020

25. Stubbs J, Liu S, Quarles LD. Role of fibroblast growth factor 23 in phosphate homeostasis and pathogenesis of disordered mineral metabolism in chronic kidney disease. Semin Dial 2007;20(4):302-308

26. Fukagawa M, Kazama JJ. FGF23: its role in renal bone disease. Pediatr Nephrol 2006;21(12):1802-1806

27. Gutierrez OM, Mannstadt M, Isakova T et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008;359(6):584-592

28. Rodriguez M, Nemeth E, Martin D. The calcium-sensing receptor: a key factor in the pathogenesis of secondary hyperparathyroidism. Am J Physiol Renal Physiol 2005; 288(2): F253-264

29. Fukuda N, Tanaka H, Tominaga Y et al. Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest 1993;92(3):1436-1443

30. Kifor O, Moore FD Jr, Wang P et al. Reduced immunostaining for the extracellular Ca2+-sensing receptor in primary and uremic secondary hyperparathyroidism. J Clin Endocrinol Metab 1996;81(4):1598-1606

31. Gogusev J, Duchambon P, Hory B et al. Depressed expression of calcium receptor in parathyroid gland tissue of patients with hyperparathyroidism. Kidney Int 1997;51(1):328-336

32. Craver L, Marco MP, Martinez I et al. Mineral metabolism parameters throughout chronic kidney disease stages 1-5—achievement of K/DOQI target ranges. Nephrol Dial Transplant 2007;22(4):1171-1176

33. Gutierrez O, Isakova T, Rhee E et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 2005;16(7):2205-2215

34. Berndt T, Kumar R. Phosphatonins and the regulation of phosphate homeostasis. Annu Rev Physiol 2007;69:341-359

35. Liu S, Quarles LD. How fibroblast growth factor 23 works. J Am Soc Nephrol 2007;18(6):1637-1647

36. Shigematsu T, Kazama JJ, Yamashita et al. Possible involvement of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism associated with renal insufficiency. Am J Kidney Dis 2004;44(2):250-256

37. Shimada T, Hasegawa H, Yamazaki Y et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004;19(3):429-435

38. Coburn JW, Popovtzer MM, Massry SG, Kleeman CR. The physicochemical state and renal handling of divalent ions in chronic renal failure. Arch Intern Med 1969;124(3):302-311

39. Coburn JW, Koppel MH, Brickman AS, Massry SG. Study of intestinal absorption of calcium in patients with renal failure. Kidney Int 1973;3(4):264-272

40. Popovtzer MM, Schainuck LI, Massry SG, Kleeman CR. Divalent ion excretion in chronic kidney disease: relation to degree of renal insufficiency. Clin Sci 1970;38(3):297-307

41. Goodman WG, Quarles LD. Development and progression of secondary hyperparathyroidism in chronic kidney disease: lessons from molecular genetics. Kidney Int 2008; 74(3):276-288

42. Bricker NS. On the pathogenesis of the uremic state. An exposition of the «trade-off hypothesis». N Engl J Med 1972; 286(20):1093-1099

43. Slatopolsky E, Bricker NS. The role of phosphorus restriction in the prevention of secondary hyperparathyroidism in chronic renal disease. Kidney Int 1973;4(2):141-145

44. Kohlhagen J, Kelly J. Prevalence of vascular risk factors and vascular disease in predialysis chronic renal failure. Nephrology (Carlton)2003;8(6):274-279

45. Kestenbaum B, Sampson JN, Rudser KD et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol 2005;16(2):520-528

46. Voormolen N, Noordzij M, Grootendorst DC et al. High plasma phosphate as a risk factor for decline in renal function and mortality in pre-dialysis patients. Nephrol Dial Transplant 2007;22(10):2909-2916

47. Kuro-o M. Klotho as a regulator of fibroblast growth factor signaling and phosphate/calcium metabolism. Curr Opin Nephrol Hypertens 2006;15(4):437-441

48. Morishita K, Shirai A, Kubota M et al. The progression of aging in klotho mutant mice can be modified by dietary phosphorus and zinc. J Nutr 2001;131(12):3182-3188

49. Волков ММ, Дегтерева ОА, Шевякова ЕВ. Факторы, связанные с кальцинацией клапанного аппарата сердца у пациентов на хроническом гемодиализе. Нефрология 2007;11(3):57-63

50. Joy MS, Karagiannis PC, Peyerl FW. Outcomes of secondary hyperparathyroidism in chronic kidney disease and the direct costs of treatment. J Manag Care Pharm 2007; 13(5): 397-411

51. Block GA, Klassen PS, Lazarus JM et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 2004;15(8):2208-2218

52. Kovesdy CP, Ahmadzadeh S, Anderson JE, Kalantar-Zadeh K. Secondary hyperparathyroidism is associated with higher mortality in men with moderate to severe chronic kidney disease. Kidney Int 2008;73(11):1296-1302

53. Covic A, Kothawala P, Bernal M et al. Systematic review of the evidence underlying the association between mineral metabolism disturbances and risk of all-cause mortality, cardiovascular mortality and cardiovascular events in chronic kidney disease. Nephrol Dial Transplant 2008 Nov 11. [Epub ahead of print]

54. Tentori F, Blayney MJ, Albert JM et al. Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2008;52(3):519-530

55. Moe SM. Vascular calcification and renal osteodystrophy relationship in chronic kidney disease. Eur J Clin Invest 2006; 36 (Suppl 2):51-62

56. Wang AY, Woo J, Wang M et al. Association of inflammation and malnutrition with cardiac valve calcification in continuous ambulatory peritoneal dialysis patients. J Am Soc Nephrol 2001;12(9):1927-1936.

57. Nasri H, Baradaran A. Close Association between parathyroid hormone and left ventricular function and structure in end-stage renal failure patients under maintenance hemodialysis. J Ayub Med Coll Abbottabad 2004;16(2): 3-8

58. Lemmila S, Saha H, Virtanen V et al. Effect of intravenous calcitriol on cardiac systolic and diastolic function in patients on hemodialysis. Am J Nephrol 1998;18(5):404-410

59. Wanic-Kossowska M, Lehmann P, Czekalski S. Left ventricular systolic and diastolic dysfunction in patients with chronic renal failure treated with hemodialysis. Pol Arch Med Wewn 2003;109(4):365-373

60. Kostic S, Veljkovic S, Cekic S et al. The effect of parathormone on arterial blood pressure in patients on hemodialysis. Srp Arh Celok Lek 1996;124 [Suppl 1]:115-116

61. Jorde R, Svartberg J, Sundsfjord J. Serum parathyroid hormone as a predictor of increase in systolic blood pressure in men. J Hypertens 2005;23(9):1639-1644

62. Letizia C, Ferrari P, Cotesta D et al. Ambulatory monitoring of blood pressure (AMBP) in patients with primary hyperparathyroidism. J Hum Hypertens 2005;19(11): 901-906

63. Dalberg K, Brodin LA, Juhlin-Dannfelt A, Farnebo LO. Cardiac function in primary hyperparathyroidism before and after operation. An echocardiographic study. Eur J Surg 1996; 162(3):171-176

64. Evenepoel P, Claes K, Kuypers D et al. Impact of parathyroidectomy on renal graft function, blood pressure and serum lipids in kidney transplant recipients: a single centre study. Nephrol Dial Transplant 2005; 20(8):1714-1720

65. Pajda M, Matug A, Widlak M et al. Influence of parathyroidectomy on blood pressure and function of the transplanted kidney in patients with tertiary hyperparathyroidism. Ann Transplant 2006;11(1):11-15

66. Iqbal A, Jorde R, Lunde P et al. Left ventricular dysfunction in subjects with mild secondary hyperparathyroidism detected with pulsed wave tissue Doppler echocardiography. Cardiology 2006;105(1):1-8.

67. Волков ММ, Смирнов АВ, Дегтерева ОА, Шевякова ЕВ. Дисфункции миокарда, оцениваемые методом тканевой допплерографии и фосфорно-кальциевый баланс у пациентов на хроническом гемодиализе. Нефрология 2008; 12(3):18-23

68. Goto N, Tominaga Y, Matsuoka S et al. Cardiovascular complications caused by advanced secondary hyperparathyroidism in chronic dialysis patients; special focus on dilated cardiomyopathy. Clin Exp Nephrol 2005; 9(2):138-141

69. Ohara N, Hiramatsu K, Shigematsu S et al. Effect of parathyroid hormone on left ventricular diastolic function in patients with primary hyperparathyroidism. Miner Electrolyte Metab 1995; 21(1-3):63-66

70. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis(2003) 42:S1–S201

71. Fukagawa M, Okazaki R, Takano K et al. Regression of parathyroid hyperplasia by calcitriol-pulse therapy in patients on long-term dialysis. N Engl J Med 1990;323(6):421-422

72. Gallieni M, Brancaccio D, Padovese P et al. Low-dose intravenous calcitriol treatment of secondary hyperparathyroidism in hemodialysis patients. Italian Group for the Study of Intravenous Calcitriol. Kidney Int 1992; 42(5): 1191-1198

73. Tan AU Jr, Levine BS, Mazess RB et al. Effective suppression of parathyroid hormone by 1 alpha-hydroxy-vitamin D2 in hemodialysis patients with moderate to severe secondary hyperparathyroidism. Kidney Int 1997;51(1):317-323

74. Chertow GM, Burke SK, Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 2002;62(1):245-252

75. McCullough PA, Sandberg KR, Dumler F, Yanez JE. Determinants of coronary vascular calcification in patients with chronic kidney disease and end-stage renal disease: a systematic review. J Nephrol 2004;17(2):205-215

76. Tominaga Y, Inaguma D, Matsuoka S et al. Is the volume of the parathyroid gland a predictor of Maxacalcitol response in advanced secondary hyperparathyroidism? Ther Apher Dial 2006;10(2):198-204

77. Bas A, Lopez I, Perez J et al. Reversibility of calcitriol-induced medial artery calcification in rats with intact renal function. J Bone Miner Res 2006;21(3):484-490

78. Niederhoffer N, Bobryshev YV, Lartaud-Idjouadiene I et al. Aortic calcification produced by vitamin D3 plus nicotine. J Vasc Res 1997;34(5):386-398

79. Brown EM, Gamba G, Riccardi D et al. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 1993;366(6455):575-580

80. DruekeTB. Modulation and action of the calcium-sensing receptor. Nephrol Dial Transplant 2004;19 Suppl 5:V20-26

81. Nagano N, Nemeth EF. Functional proteins involved in regulation of intracellular Ca(2+) for drug development: the extracellular calcium receptor and an innovative medical approach to control secondary hyperparathyroidism by calcimimetics. J Pharmacol Sci 2005;97(3):355-360

82. DruekeTB. Modulation and action of the calcium-sensing receptor. Nephrol Dial Transplant 2004;19 Suppl 5:V20-V26

83. Levi R, Ben-Dov IZ, Lavi-Moshayoff V et al. Increased Parathyroid Hormone Gene Expression in Secondary Hyperparathyroidism of Experimental Uremia Is Reversed by Calcimimetics: Correlation with Posttranslational Modification of the Trans Acting Factor AUF1. J Am Soc Nephrol 2006; 17(1): 107-112

84. Rodriguez ME, Almaden Y, Canadillas S et al. The calcimimetic R-568 increases vitamin D receptor expression in rat parathyroid glands. Am J Physiol Renal Physiol 2007; 292(5): F1390-1395

85. Huang C, Miller RT. Regulation of renal ion transport by the calcium-sensing receptor: an update. Curr Opin Nephrol Hypertens 2007;16(5):437-443

86. Smajilovic S, Tfelt-Hansen J. Calcium acts as a first messenger through the calcium-sensing receptor in the cardiovascular system. Cardiovasc Res 2007;75(3):457-467

87. Tfelt-Hansen J, Brown EM. The calcium-sensing receptor in normal physiology and pathophysiology: a review. Crit Rev Clin Lab Sci 2005;42(1):35-70

88. Goodman WG, Hladik GA, Turner SA et al. The Calcimimetic agent AMG 073 lowers plasma parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism. J Am Soc Nephrol 2002;13(4):1017-1024

89. Shoback DM, Bilezikian JP, Turner SA et al. The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism. J Clin Endocrinol Metab 2003; 88(12):5644-5649

90. Quarles LD, Sherrard DJ, Adler S et al. The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease. J Am Soc Nephrol 2003;14(3):575-583

91. Block GA, Martin KJ, de Francisco AL et al. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 2004;350(15):1516-1525

92. Peacock M, Bilezikian JP, Klassen PS et al. Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 2005; 90(1):135-141

93. Moe SM, Cunningham J, Bommer J et al. Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl. Nephrol Dial Transplant 2005; 20(10):2186-2193

94. 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(3):800-807

95. Chertow GM, Blumenthal S, Turner S et al. Cinacalcet hydrochloride (Sensipar) in hemodialysis patients on active vitamin D derivatives with controlled PTH and elevated calcium x phosphate. Clin J Am Soc Nephrol 2006;1(2):305-312

96. Fukagawa M, Yumita S, Akizawa T et al. Cinacalcet (KRN1493) effectively decreases the serum intact PTH level with favorable control of the serum phosphorus and calcium levels in Japanese dialysis patients. Nephrol Dial Transplant 2008;23(1):328-335

97. Messa P, Macario F, Yaqoob M et al. The OPTIMA study: assessing a new cinacalcet (Sensipar/Mimpara) treatment algorithm for secondary hyperparathyroidism. Clin J Am Soc Nephrol 2008;3(1):36-45

98. Evenepoel P. Calcimimetics in chronic kidney disease: evidence, opportunities and challenges. Kidney Int 2008; 74(3): 265-275

99. Nagano N. Pharmacological and clinical properties of calcimimetics: calcium receptor activators that afford an innovative approach to controlling hyperparathyroidism. Pharmacol Ther 2006;109(3):339-365

100. Moe SM, Chertow GM, Coburn JW et al. Achieving NKF-K/DOQI bone metabolism and disease treatment goals with cinacalcet HCl. Kidney Int 2005;67(2):760-771

101. Arenas MD, Alvarez-Ude F, Gil MT et al. Implementation of ‘K/DOQI Clinical Practice Guidelines 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(6):1639-1644

102. Coen G, Calabria S, Bellinghieri G et al. Parathyroidectomy in chronic renal failure: short- and long- term results on parathyroid function, blood pressure and anemia. Nephron 2001;88(2):149-155

103. Saunders RN, Karoo R, Metcalfe MS, Nicholson ML. Four gland parathyroidectomy without reimplantation in patients with chronic renal failure. Postgrad Med J 2005;81(954):255-258

104. Parfitt AM. Hypercalcemic hyperparathyroidism following renal transplantation: differential diagnosis, management, and implications for cell population control in the parathyroid gland. Miner Electrolyte Metab 1982;8(2):92-112

105. Fukagawa M, Nakanishi S, Kazama JJ. Basic and clinical aspects of parathyroid hyperplasia in chronic kidney disease. Kidney Int Suppl 2006;(102):S3-7

106. Tominaga Y, TanakaYet al. Histopathology, pathophysiology, and indications for surgical treatment of renal hyperparathyroidism. Semin Surg Oncol 1997;13:78-86

107. Drueke T, Martin D, Rodriguez M. Can calcimimetics inhibit parathyroid hyperplasia? Evidence from preclinical studies. Nephrol Dial Transplant 2007;22(7):1828-1839

108. Wada M, Furuya Y, Sakiyama J et al. The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency. Control of parathyroid cell growth via a calcium receptor. J Clin Invest 1997;100(12):2977-2983

109. Colloton M, Shatzen E, Miller G et al. Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism. Kidney Int 2005;67(2):467-476

110. Mizobuchi M, Ogata H, Hatamura I et al. Activation of calcium-sensing receptor accelerates apoptosis in hyperplastic parathyroid cells. Biochem Biophys Res Commun 2007;362(1):11-16

111. 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(3):982-989

112. Komaba H, Fukagawa M. Regression of parathyroid hyperplasia by calcimimetics—fact or illusion? Nephrol Dial Transplant 2009;24(3):707-709

113. Terawaki H, Nakano H, Takeguchi F et al. Regression of parathyroid gland swelling by treatment with cinacalcet. Nephrol Dial Transplant 2008;23(1):328-335

114. Chin J, Miller SC, Wada M et al. Activation of the calcium receptor by a calcimimetic compound halts the progression of secondary hyperparathyroidism in uremic rats. J Am Soc Nephrol 2000;11(5):903-911

115. Mizobuchi M, Hatamura I, Ogata H et al. Calcimimetic compound upregulates decreased calcium-sensing receptor expression level in parathyroid glands of rats with chronic renal insufficiency. J Am Soc Nephrol 2004;15(10):2579-2587

116. Cunningham J, Danese M, Olson K et al. Effects of the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism. Kidney Int 2005;68(4):1793-1800

117. Jadoul M, Albert JM, Akiba T et al. Incidence and risk factors for hip or other bone fractures among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study. Kidney Int 2006;70(7):1358-1366

118. Alem AM, Sherrard DJ, Gillen DL et al. Increased risk of hip fracture among patients with end-stage renal disease. Kidney Int 2000;58(1):396-399

119. Jadoul M. Towards the prevention of bone fractures in dialysed patients? Nephrol Dial Transplant 2007;22(12):3377-3380

120. Wada M, Ishii H, Furuya Y et al. NPS R-568 halts or reverses osteitis fibrosa in uremic rats. Kidney Int 1998; 53(2): 448-453

121. Lien YH, Silva AL, Whittman D. Effects of cinacalcet on bone mineral density in patients with secondary hyperparathyroidism. Nephrol Dial Transplant 2005;20(6):1232-1237

122. Добронравов ВА, Волков ММ, Мнускина ММ и др. Фосфорно-кальциевый баланс и минеральная плотность костей различных отделов скелета у больных на хроническом гемодиализе. Нефрология 2006; 10(4):31-36

123. Kawata T, Nagano N, Obi M et al. Cinacalcet suppresses calcification of the aorta and heart in uremic rats. Kidney Int 2008;74(10):1229-1231

124. Malluche HH, Monier-Faugere MC, Wang G et al. An assessment of cinacalcet HCl effects on bone histology in dialysis patients with secondary hyperparathyroidism. Clin Nephrol 2008;69(4):269-278

125. Sherrard DJ, Hercz G, Pei Y et al. The spectrum of bone disease in end-stage renal failure—an evolving disorder. Kidney Int 1993;43(2):436-442

126. Mucsi I, Hercz G. Relative hypoparathyroidism and adynamic bone disease. Am J Med Sci 1999;317(6):405-409

127. Couttenye MM, D’Haese PC, Van Hoof VO et al. Low serum levels of alkaline phosphatase of bone origin: a good marker of adynamic bone disease in haemodialysis patients. Nephrol Dial Transplant 1996;11(6):1065-1072

128. Spasovski GB, Bervoets AR, Behets GJ et al. Nephrol Dial Transplant 2003;18(6):1159-1166

129. Pei Y, Hercz G, Greenwood C et al. Risk factors for renal osteodystrophy: a multivariant analysis. J Bone Miner Res 1995;10(1):149-156

130. Qi Q, Monier-Faugere MC, Geng Z, Malluche HH. Predictive value of serum parathyroid hormone levels for bone turnover in patients on chronic maintenance dialysis. Am J Kidney Dis 1995;26(4):622-631

131. Malluche HH, Monier-Faugere MC. Risk of adynamic bone disease in dialyzed patients. Kidney Int Suppl 1992;38:S62-67

132. London GM, Marty C, Marchais SJ et al. Arterial calcifications and bone histomorphometry in end-stage renal disease. J Am Soc Nephrol 2004;15(7):1943-1951

133. Danese MD, Kim J, Doan QV et al. PTH and the risks for hip, vertebral, and pelvic fractures among patients on dialysis. Am J Kidney Dis 2006;47(1):149-156

134. Coco M, Rush H. Increased incidence of hip fractures in dialysis patients with low serum parathyroid hormone. Am J Kidney Dis 2000;36(6):1115-1121

135. Ishii H, Wada M, Furuya Y et al. Daily intermittent decreases in serum levels of parathyroid hormone have an anabolic-like action on the bones of uremic rats with low-turnover bone and osteomalacia. Bone 2000;26(2):175-182

136. Price PA, Roublick AM, Williamson MK. Artery calcification in uremic rats is increased by a low protein diet and prevented by treatment with ibandronate. Kidney Int 2006;70(9):1577-1583

137. Coen G, Manni M, Mantella D et al. Are PTH serum levels predictive of coronary calcifications in haemodialysis patients? Nephrol Dial Transplant 2007;22(11):3262-3267

138. Neves KR, Graciolli FG, dos Reis LM et al. Vascular calcification: contribution of parathyroid hormone in renal failure. Kidney Int 2007;71(12):1262-1270

139. Henley C, Colloton M, Cattley RC et al. 1,25-Dihydroxyvitamin D3 but not cinacalcet HCl (Sensipar/Mimpara) treatment mediates aortic calcification in a rat model of secondary hyperparathyroidism. Nephrol Dial Transplant 2005;20(7):1370-1377

140. Lopez I, Mendoza FJ, Aguilera-Tejero E et al. The effect of calcitriol, paricalcitol, and a calcimimetic on extraosseous calcifications in uremic rats. Kidney Int 2008;73(3):300-307

141. Rodriguez M, Aguliera-Tejero E, Mendoza FJ et al. Effects of calcimimetics on extraskeletal calcifications in chronic kidney disease. Kidney Int 2008;74(Suppl 111):s50-s54

142. Lopez I, Aguilera-Tejero E, Mendoza FJ et al. Calcimimetic R-568 decreases extraosseous calcifications in uremic rats treated with calcitriol. J Am Soc Nephrol 2006;17(3):795-804

143. Molostvov G, James S, Fletcher S et al. Extracellular calcium-sensing receptor is functionally expressed in human artery. Am J Physiol Renal Physiol 2007;293(3):F946-955

144. Wonneberger K, Scofield MA, Wangemann P. Evidence for a calcium-sensing receptor in the vascular smooth muscle cells of the spiral modiolar artery. J Membr Biol 2000;175(3):203-212

145. Murshed M, Schinke T, McKee MD, Karsenty G. Extracellular matrix mineralization is regulated locally; different roles of two gla-containing proteins. J Cell Biol 2004;165(5):625-630

146. Luo G, Ducy P, McKee MD et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 1997;386(6620):78-81

147. Koleganova N, Piecha G, Ritz E et al. A calcimimetic (R-568), but not calcitriol, prevents vascular remodeling in uremia. Kidney Int 2009;75(1):60-71

148. Jono S, McKee MD, Murry CE et al. Phosphate regulation of vascular smooth muscle cell calcification. Circ Res 2000 29;87(7):E10-17

149. Mizobuchi M, Finch JL, Martin DR, Slatopolsky E. Differential effects of vitamin D receptor activators on vascular calcification in uremic rats. Kidney Int 2007;72(6):709-715

150. Moe SM, Reslerova M, Ketteler M et al. Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD). Kidney Int 2005; 67(6):2295-2304

151. Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circ Res 2004;95(11):1046-1057

152. Demer LL, Tintut Y. Pitting phosphate transport inhibitors against vascular calcification. Circ Res 2006; 98(7): 857-859

153. Tamura K, Suzuki Y, Matsushita M et al. Prevention of aortic calcification by etidronate in the renal failure rat model. Eur J Pharmacol 2007;558(1-3):159-166

154. Li X, Yang HY, Giachelli CM. Role of the sodium-dependent phosphate cotransporter, Pit-1, in vascular smooth muscle cell calcification. Circ Res 2006;98(7):905-912

155. Shiraishi N, Kitamura K, Miyoshi T et al. Successful treatment of a patient with severe calcific uremic arteriolopathy (calciphylaxis) by etidronate disodium. Am J Kidney Dis 2006;48(1):151-154

156. Cicone JS, Petronis JB, Embert CD, Spector DA. Successful treatment of calciphylaxis with intravenous sodium thiosulfate. Am J Kidney Dis 2004;43(6):1104-1108

157. Meissner M, Bauer R, Beier C et al. Sodium thiosulphate as a promising therapeutic option to treat calciphylaxis. Dermatology 2006;212(4):373-376

158. Brucculeri M, Cheigh J, Bauer G, Serur D. Long-term intravenous sodium thiosulfate in the treatment of a patient with calciphylaxis. Semin Dial 2005;18(5):431-434

159. Guerra G, Shah RC, Ross EA. Rapid resolution of calciphylaxis with intravenous sodium thiosulfate and continuous venovenous haemofiltration using low calcium replacement fluid: case report. Nephrol Dial Transplant 2005;20(6):1260-1262

160. Velasco N, MacGregor MS, Innes A, MacKay IG. Successful treatment of calciphylaxis with cinacalcet-an alternative to parathyroidectomy? Nephrol Dial Transplant 2006; 21(7):1999-2004

161. Гавриленков ПВ. Особенности фосфорно-кальциевого обмена у больных хронической почечной недостаточностью, получающих лечение хроническим гемодиализом. Дисс. …канд. мед. наук.– СПб, 2002

162. Zerbi S, Ruggiero P, Pedrini LA. Massive soft tissue calcifications and cinacalcet. J Clin Endocrinol Metab 2008; 93(4):1121-1122

163. Ohanian J, Gatfield KM, Ward DT, Ohanian V. Evidence for a functional calcium-sensing receptor that modulates myogenic tone in rat subcutaneous small arteries. Am J Physiol Heart Circ Physiol 2005;288(4):H1756-1762

164. Ortiz-Capisano MC, Ortiz PA, Garvin JL et al. Expression and function of the calcium-sensing receptor in juxtaglomerular cells. Hypertension 2007;50(4):737-743

165. Verdecchia P, Angeli F, Mazzotta G et al. The renin angiotensin system in the development of cardiovascular disease: role of aliskiren in risk reduction. Vasc Health Risk Manag 2008;4(5):971-981

166. Smajilovic S, Sheykhzade M, Holmegard HN et al. Calcimimetic, AMG 073, induces relaxation on isolated rat aorta. Vascul Pharmacol 2007;47(4):222-228

167. Ziegelstein RC, Xiong Y, He C, Hu Q. Expression of a functional extracellular calcium-sensing receptor in human aortic endothelial cells. Biochem Biophys Res Commun 2006; 342(1):153-163

168. Odenwald T, Nakagawa K, Hadtstein C et al. Acute blood pressure effects and chronic hypotensive action of calcimimetics in uremic rats. J Am Soc Nephrol 2006;17(3):655-662

169. Nyirenda MJ, Padfield PL. Parathyroid hormone and hypertension. J Hypertens 2005;23(9):1633-1634

170. LindbergJS. Calcimimetics: a new tool for management of hyperparathyroidism and renal osteodystrophyin patients with chronic kidney disease. Kidney Int Suppl 2005; (95):S33-S36

171. Akmal M, Kasim SE, Soliman AR, Massry SG. Excess parathyroid hormone adversely affects lipid metabolism in chronic renal failure. Kidney Int 1990;37(3):854-858

172. Klin M, Smogorzewski M, Ni Z et al. Abnormalities in hepatic lipase in chronic renal failure: role of excess parathyroid hormone. J Clin Invest 1996;97(10):2167-2173

173. Roullet JB, Lacour B, Yvert JP, Drueke T. Correction by insulin of disturbed TG-rich LP metabolism in rats with chronic renal failure. Am J Physiol 1986;250(4 Pt 1):E373-376

174. Chertow GM, Pupim LB, Block GA et al. Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE): rationale and design overview. Clin J Am Soc Nephrol 2007; 2(5):898-905

175. Ogata H, Ritz E, Odoni G et al. Beneficial effects of calcimimetics on progression of renal failure and cardiovascular risk factors. J Am Soc Nephrol 2003;14(4):959-967

176. Massfelder T, Parekh N, Endlich K et al. Effect of intrarenally infused parathyroid hormone-related protein on renal blood flow and glomerular filtration rate in the anaesthetized rat. Br J Pharmacol 1996;118(8):1995-2000

177. Lau K. Phosphate excess and progressive renal failure: the precipitation-calcification hypothesis. Kidney Int 1989; 36(5): 918-937

178. Khan SR. Crystal-induced inflammation of the kidneys: results from human studies, animal models, and tissue-culture studies. Clin Exp Nephrol 2004;8(2):75-88

179. Pattaragarn A, Fox J, Alon US. Effect of the calcimimetic NPS R-467 on furosemide-induced nephrocalcinosis in the young rat. Kidney Int 2004;65(5):1684-1689

180. Schwarz U, Amann K, Orth SR et al. Effect of 1,25 (OH)2 vitamin D3 on glomerulosclerosis in subtotally nephrectomized rats. Kidney Int 1998;53(6):1696-1705

181. Agarwal R, Acharya M, Tian J et al. Antiproteinuric effect of oral paricalcitol in chronic kidney disease. Kidney Int 2005;68(6):2823-2828

182. Piecha G, Kokeny G, Nakagawa K et al. Calcimimetic R-568 or calcitriol: equally beneficial on progression of renal damage in subtotally nephrectomized rats. Am J Physiol Renal Physiol 2008;294(4):F748-57

183. Смирнов АВ, Волков ММ, Добронравов ВА. Кардиопротективные эффекты D-гормона: обзор литературы и собственные данные. Нефрология 2009;13(1):

184. Смирнов АВ, Волков ММ. Роль витамина D в замедлении прогрессирования хронической болезни почек. Нефрология 2008;12(4):20-27

185. Ishimura E, Nishizawa Y, Inaba M et al. Serum levels of 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, and 25-hydroxyvitamin D in nondialyzed patients with chronic renal failure. Kidney Int 1999;55(3):1019-1027

186. Martin KJ, Gonzalez EA, Gellens M et al. 19-Nor-1-alpha-25-dihydroxyvitamin D2 (Paricalcitol) safely and effectively reduces the levels of intact parathyroid hormone in patients on hemodialysis. J Am Soc Nephrol 1998;9(8):1427-1432

187. Berl T, Berns AS, Hufer WE et al. 1,25 dihydroxycholecalciferol effects in chronic dialysis. A double-blind controlled study. Ann Intern Med 1978;88(6):774-780

188. Brown AJ, Dusso A, Slatopolsky E. Vitamin D. Am J Physiol 1999;277(2 Pt 2):F157-175

189. Khajehdehi P, Taheri S. Effect of oral calcitriol pulse therapy on the lipid, calcium, and glucose homeostasis of hemodialysis-patients: its safety in a combination with oral calcium carbonate. J Ren Nutr 2003;13(2):78-83

190. Koshikawa S, Akizawa T, Kurokawa K et al. Clinical effect of intravenous calcitriol administration on secondary hyperparathyroidism. A double-blind study among 4 doses. Nephron 2002;90(4):413-423

191. Moe SM, Zekonis M, Harezlak J et al. A placebo-controlled trial to evaluate immunomodulatory effects of paricalcitol. Am J Kidney Dis 2001;38(4):792-802

192. Akizawa T, Ohashi Y, Akiba T et al. Dose-response study of 22-oxacalcitriol in patients with secondary hyperparathyroidism. Ther Apher Dial 2004;8(6):480-491

193. Goodman WG. Recent developments in the management of secondary hyperparathyroidism. Kidney Int 2001; 59(3):1187-1201

194. Raggi P, Boulay A, Chasan-Taber S et al. 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

195. Malluche HH, Monier-Faugere MC, Koszewski NJ. Use and indication of vitamin D and vitamin D analogues in patients with renal bone disease. Nephr Dial Transpl 2002;17 (suppl 10):6-9

196. Matias PJ, Ferreira C, Jorge C et al. 25-Hydroxyvitamin D3, arterial calcifications and cardiovascular risk markers in haemodialysis patients. Nephrol Dial Transplant 2009; 24(2): 611-618

197. Martin KJ, Gonzalez EA. Vitamin D analogues for the management of secondary hyperparathyroidism. Am J Kidney Dis 2001;38(5 Suppl 5):S34-40

198. Takahashi F, Finch JL, Denda M et al. A new analog of 1,25-(OH)2D3, 19-NOR-1,25-(OH)2D2, suppresses serum PTH and parathyroid gland growth in uremic rats without elevation of intestinal vitamin D receptor content. Am J Kidney Dis 1997; 30(1):105-112

199. Sprague SM, Llach F, Amdahl M et al. Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. Kidney Int 2003;63(4):1483-1490

200. Cunningham J. Achieving therapeutic targets in the treatment of secondary hyperparathyroidism. Nephrol Dial Transplant 2004;19 Suppl 5:V9-14

201. Gonzalez M, Hutchison A, Girndt M et al. Secondary hyperparathyroidism (HPT) in patients receiving peritoneal dialysis (PD) can be effectively managed with cinacalcet (Mimpara/Sensipar). [Abstract SP359]. Presented at: ERA-EDTA Congress, 15–18 July 2006, Glasgow, UK

202. Messa P, Villa G, Braun J et al. The OPTIMA study: lower doses of cinacalcet (Mimpara/Sensipar) are required to achieve KDOQI secondary hyperparathyroidism (HPT) targets in patients with less severe disease. [Abstract and Presentation MP324]. Presented at: ERA-EDTA Congress, 15–18 July 2006, Glasgow, UK

203. Wilkie M, Salvadori M, De Meester J et al. The OPTIMA study: optimising the dose of vitamin D (vit D) in the presence of cinacalcet (Mimpara/Sensipar) to obtain maximum clinical benefit. [Abstract SP358]. Presented at: ERA-EDTA Congress, 15–18 July 2006, Glasgow, UK

204. Locatelli F, Macario F, Brink H et al. The OPTIMA study; efficacy of cinacalcet (Mimpara/Sensipar) treatment algorithm to treat dialysis patients with elevated PTH and calcium–phosphorus product (Ca x P). [Abstract SP357]. Presented at: ERA-EDTA Congress, 15–18 July 2006, Glasgow, UK

205. Messa P, Sindici C, Cannella G et al. Persistent secondary hyperparathyroidism after renal transplantation. Kidney Int 1998;54(5):1704-1713

206. Bonarek H, Merville P, Bonarek M et al. Reduced parathyroid functional mass after successful kidney transplantation. Kidney Int 1999;56(2):642-649

207. Evenepoel P, Naesens M, Claes K et al. Tertiary ‘hyperphosphatoninism’ accentuates hypophosphatemia and suppresses calcitriol levels in renal transplant recipients. Am J Transplant 2007;7(5):1193-200

208. Evenepoel P, Claes K, Kuypers D et al. Natural history of parathyroid function and calcium metabolism after kidney transplantation: a single-centre study. Nephrol Dial Transplant 2004;19(5):1281-1287

209. Reinhardt W, Bartelworth H, Jockenhovel F et al. Sequential changes of biochemical bone parameters after kidney transplantation. Nephrol Dial Transplant 1998;13(2):436-442

210. Ghanekar H, Welch BJ, Moe OW, Sakhaee K. Post-renal transplantation hypophosphatemia: a review and novel insights. Curr Opin Nephrol Hypertens 2006;15(2):97-104

211. Heaf JG. Bone disease after renal transplantation. Transplantation 2003;75(3):315-325

212. Sperschneider H, Stein G. Bone disease afterrenal transplantation. Nephrol Dial Transplant 2003;18(5):874-877

213. Gwinner W, Suppa S, Mengel M et al. Early calcification of renal allografts detected by protocol biopsies: causes and clinical implications. Am J Transplant 2005;5(8):1934-1941

214. Serra AL, Savoca R, Huber AR et al. Effective control of persistent hyperparathyroidism with cinacalcet in renal allograft recipients. Nephrol Dial Transplant 2007;22(2):577-583

215. Kruse AE, Eisenberger U, Frey FJ, Mohaupt MG. Nephrol Dial Transplant 2007;22(8):2362-2365

216. Srinivas TR, Schold JD, Womer KL et al. Improvement in hypercalcemia with cinacalcet after kidney transplantation. Clin J Am Soc Nephrol 2006;1(2):323-326

217. Leca N, Laftavi M, Gundroo A et al. Early and severe hyperparathyroidism associated with hypercalcemia after renal transplant treated with cinacalcet. Am J Transplant 2006; 6(10): 2391-2395

218. El-Amm JM, Doshi MD, Singh A et al. Preliminary experience with cinacalcet use in persistent secondary hyperparathyroidism after kidney transplantation. Transplantation 2007;83(5):546-549

219. Szwarc I, Argiles A, Garrigue V et al. Cinacalcet chloride is efficient and safe in renal transplant recipients with posttransplant hyperparathyroidism. Transplantation 2006; 82(5):675-680

220. Bergua C, Torregrosa JV, Cofan F, Oppenheimer F. Cinacalcet for the treatment of hypercalcemia in renal transplanted patients with secondary hyperparathyroidism. Transplant Proc 2007;39(7):2254-2255

221. Borchhardt KA, Heinzl H, Mayerwoger E et al. Cinacalcet increases calcium excretion in hypercalcemic hyperparathyroidism after kidney transplantation. Transplantation 2008;86(7):919-924

222. Brown EM, Hebert SC. Calcium-receptor-regulated parathyroid and renal function. Bone 1997;20(4):303-309

223. Bergua C, Torregrosa JV, Fuster D et al. Effect of cinacalcet on hypercalcemia and bone mineral density in renal transplanted patients with secondary hyperparathyroidism. Transplantation 2008;86(3):413-417

224. Falck P, Vethe NT, Asberg A et al. Cinacalcet’s effect on the pharmacokinetics of tacrolimus, cyclosporine and mycophenolate in renal transplant recipients. Nephrol Dial Transplant 2008;23(3):1048-1053

225. Schwarz A, Rustien G, Merkel S et al. Decreased renal transplant function after parathyroidectomy. Nephrol Dial Transplant 2007;22(2):584-591

226. Evenepoel P, Claes K, Kuypers DR et al. Parathyroidectomy after successful kidney transplantation: a single centre study. Nephrol Dial Transplant 2007;22(6):1730-1737

227. Thervet E, Legendre C, Beaune P, Anglicheau D. Cytochrome P450 3A polymorphisms and immunosuppressive drugs. Pharmacogenomics 2005;6(1):37-47

228. Charytan C, Coburn JW, Chonchol M et al. Cinacalcet hydrochloride is an effective treatment for secondary hyperparathyroidism in patients with CKD not receiving dialysis. Am J Kidney Dis 2005;46(1):58-67

229. Chonchol M, Locatelli F, Abboud HE et al. 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 2008 Dec 23. [Epub ahead of print]