Also, the increase of calcification in the aortic valve was significantly less in individuals treated with cinacalcet plus low-dose vitamin D, compared with those treated flexible vitamin D. These results suggest that cinacalcet plus a low dose of vitamin D sterols, compared with a flexible vitamin D regimen, may attenuate vascular and cardiac valve calcification in haemodialysis patients with moderate-to-severe SHPT.
Several studies have implicated elevated fibroblast growth factor 23 (FGF 23) levels with adverse outcomes such as refractory hyperparathyroidism, progression of renal failure, left ventricular hypertrophy, vascular calcification and also increased mortality.21–25
The exact mechanisms associated with the effect of cinacalcet on FGF 23 levels and the clinical consequences of this finding need further investigation.
studies have looked into the effect of cinacalcet treatment on FGF 23 levels. Intact FGF 23 levels were assessed in 91 patients over the course of the ACHIEVE trial, designed to compare escalating doses of cinacalcet plus fixed low-dose calcitriol analogues versus titration of vitamin D analogues alone, to suppress PTH.26,27
Treatment with cinacalcet plus low
dose calcitriol analogues resulted in lower FGF 23 levels, compared to treatment with calcitriol analogs alone in hemodialysis patients.27
Recently, serum FGF 23 levels were measured in 55 haemodialysis patients who completed a 52-week multicentre, open-label, single-arm trial examining the effectiveness of cinacalcet for treating SHPT.28 FGF-23 levels significantly decreased after 12 weeks of cinacalcet treatment, concomitantly with iPTH levels reduction. These responses were sustained for more than 52 weeks and were independent from the effects of active vitamin D.
1. Salem M, Hyperparathyroidism in the hemodialysis population: a survey of 612 patients, Am J Kidney Dis, 1997;29:862–5.
2. Young E, Akiba T, Albert J, et al., Magnitude and impact of abnormal mineral metabolism in hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS), Am J Kidney Dis, 2004;44 (Suppl. 2):34–8.
3. Sherrard DJ, Hercz G, Pei Y, et al., The spectrum of bone disease in end-stage renal failure: an evolving disorder, Kidney Int, 1993;43:436–42.
4. Block G, Klassen P, Lazarus J, et al., Mineral metabolism, mortality, and morbidity in maintenance hemodialysis, J Am Soc Nephrol, 2004;15:2208–18.
5. Guerin A, London G, Marchais S, Metivier F, Arterial stiffening and vascular calcifications in end-stage renal disease, Nephrol Dial Transplant, 2000;15:1014–21.
6. Adragão T, Pires A, Lucas C, et al., A simple vascular calcification score predicts cardiovascular risk in haemodialysis patients, Nephrol Dial Transplant, 2004;19:1480–8.
7. Moe S, Drüeke T, Management of secondary hyperparathyroidism: the importance and the challenge of controlling parathyroid hormone levels without elevating calcium, phosphorus, and calcium–phosphorus product, Am J Nephrol, 2003;23:369–79.
8. Maung H, Elangovan L, Frazao J, et al., Efficacy and side effects of intermittent intravenous and oral doxercalciferol (1alphahydroxyvitamin D2) in dialysis patients with secondary hyperparathyroidism: a sequential comparison, Am J Kidney Dis, 2001;37:532–43.
9. Goodman W, Frazão J, Goodkin D, et al., A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism, Kidney Int, 2000;58:436–45.
10. Block G, Martin K, Francisco A, et al., Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis, N Engl J Med, 2004;350:1516–25.
Soon the results of the ongoing Evaluation of cinacalcet HCl therapy to lower cardiovascular events (EVOLVE) study (ClinicalTrials.gov
identifier NCT00345839) will hopefully clarify the effect of cinacalcet treatment on cardiovascular morbidity and mortality. The purpose of this study is to evaluate the effects of cinacalcet treatment on cardiovascular events and death in CKD stage 5 dialysis patients with SHPT. The primary endpoint of the study is the time to a composite event comprising all-cause mortality or non-fatal cardiovascular events (such as myocardial infarction, hospitalisation for unstable angina, heart failure or peripheral vascular event).
The calcimimetic agent cinacalcet, in synergy with phosphate binders and possibly vitamin D, is an innovative, safe and efficacious compound that covers a previously unanswered therapeutic need in CKD stage 5 dialysis patients with SHPT. Cinacalcet treatment lowers PTH levels, with the beneficial effect of decreasing Ca and P serum levels. This compound may also have a beneficial effect on the progression of calcification. To clarify its impact on cardiovascular morbidity and mortality, the results of the ongoing EVOLVE study, which is investigating the effect of cinacalcet treatment on cardiovascular events, are clearly needed. n
11. Moe S, Chertow G, Coburn J, et al., Achieving NKF-K/DOQITM bone metabolism and disease treatment goals with cinacalcet HCL, Kidney Int, 2005;67:760–71.
12. Lindberg J, 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.
13. Moe SM, Cunningham J, Bommer J, et al., Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl, Nephrol Dial Transplant, 2005;20:2186–93.
14. Sprague SM, Evenepoel P, Curzi MP, et al., Simultaneous control of PTH and CaxP is sustained over three years of treatment with cinacalcet HCl, Clin J Am Soc Nephrol, 2009;4:1465–76.
15. Cunningham J, Urena P, Reichel H, et al., Long-term Efficacy of Cinacalcet in Secondary Hyperparathyroidism (HPT) of End Stage Renal Disease (ESRD), Presented at: ERA-EDTA Congress, Istanbul, Turkey, 4–7 June 2005: abstract SP210.
16. Frazão JM, Messa P, Mellotte GJ, et al., Cinacalcet reduces plasma intact parathyroid hormone, serum phosphate and calcium levels in patients with secondary hyperparathyroidism irrespective of its severity, Clin Nephrol, 2011;76:233–43.
17. Messa P, Macário 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;3:36–45.
18. Frazão JM, Messa P, Cunningham J, et al., Early use of cinacalcet (Mimpara®
/Sensipar® ) in dialysis patients enables
greatest achievement of NKF-KDOQI™ treatment targets for bone metabolism, Nephrol Dial Transplant, 2006;21 (Suppl. 4):iv8 (Abstract).
19. 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;68:1793–800.
20. Raggi P, Chertow GM, Torres PU, et al., The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis, Nephrol Dial Transplant, 2011;26:1327–39.
21. Kazama JJ, Sato F, Omori K, et al., Pretreatment serum FGF- 23 levels predict the efficacy of calcitriol therapy in dialysis patients, Kidney Int, 2005;67:1120–5.
22. Fliser D, Kollerits B, Neyer U, et al., Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: The mild to moderate kidney disease (MMKD) Study, J Am Soc Nephrol, 2007;18:2600–8.
23. Hsu HJ, Wu MS, Fibroblast Growth Factor 23: A possible cause of left ventricular hypertrophy in hemodialysis patients, Am J Med Sci, 2009;337:116–2.
24. Jean G, Bresson E, Terrat JC, et al., Peripheral vascular calcification in long-hemodialysis patients: associated factors and survival consequences, Nephrol Dial Transplant, 2009;24:948–55.
25. Gutierrez OM, Mannstadt M, Isakova T, et al., Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis, N Engl J Med, 2008;359:584–92.
26. Fishbane S, Shapiro WB, Corry DB, et al., Cinacalcet HCI and concurrent low-dose vitamin D improves treatment of secondary hyperparathyroidism in dialysis patients compared with vitamin D alone: The ACHIEVE study results, Clin J Am Soc Nephrol, 2008;3:1718–25.
27. Wetmore JB, Liu S, Krebill R, et al., Effects of Cinacalcet and Concurrent Low-Dose Vitamin D on FGF23 levels in ESRD, Clin J Am Soc Nephrol, 2010;5:110–6.
28. Koizumi M, Komaba H, Nakanishi S, et al., Cinacalcet treatment and serum FGF23 levels in haemodialysis patients with secondary hyperparathyroidism, Nephrol Dial Transplant, 2011;0:1–6.
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