Kalzimimetika zur Behandlung des sekundären Hyperparathyreoidismus

Zusammenfassung

Der sekundäre Hyperparathyreoidismus (sHPT) ist einer der wesentlichsten Folgen der chronischen Niereninsuffizienz. Er verursacht über den gestörten Kalzium-Phosphat-Stoff-wechsel nicht nur die Entstehung von ossären Veränderungen („renale Osteopathie”), sondern ist ebenso mitverantwortlich für extraossäre Kalzium-Phosphat-Ablagerungen, die zu einer erhöhten kardiovaskulären Morbidität und Mortalität des nierenkranken Patienten führen. Der kalziumsensible Rezeptor (CaSR) in der Nebenschilddrüse und seine therapeutische Stimulierung durch Kalzimimetika sind wichtige Stellgrößen zur Behandlung des sHPT. Für sogenannte Typ-II-Kalzimimetika (z. B. Cinacalcet) konnte die effektive und sichere Supprimierung des Parathormons und des Kalzium-Phosphat-Produktes nachgewiesen werden. Die additive niedrig dosierte Vitamin-D-Gabe sollteje doch nicht vergessen werden, da nicht nur dem Vitamin-D-Mangel, sondern auch dem schweren sHPT optimal entgegengewirkt wird. Zusammenfassend ist festzustellen, dass die Therapie mit Cinacalcet nicht nur häufiger zur Einhaltung der biochemischen Zielwerte der NKF-K/DOQI-Leitlinien führt, sondern auch die Inzidenz von kardiovaskulären Ereignissen und chirurgischen Parathyreoidektomien zu reduzieren scheint.

Summary

The secondary hyperparathyroidism (sHPT) is one of the most substantial consequences of chronic kidney disease (CKD). It is caused bya disturbanced calcium-phosphorus metabolism and responsible for the development of renal osteodystrophy as well as of extraosseous calcifications, which lead to an increased cardiovascular morbidity and mortality, in patients with CKD. The calcium-sensing receptor (CaSR) in the parathyroid glands and its therapeutic activation due to calcimimetics are important correcting variables for the treatment of sHPT. So-called type II calcimimetics (e. g. cinacalcet) are able to decrease parathyroid hormone level and calcium-phosphorus product, effectively and safely. In addition to, vitamin D metabolites should be given ina low dose to avoid vitamin D deficiency and aggravation of sHPT. In conclusion, the biochemical goal values of NKF-K/DOQI guidelines will be kept more frequently bya therapy with calcimimetic cinacalcet and the incidence of cardiovascular events and surgical parathyroidectomies seems to be reduced.

Schlüsselwörter

Chronische Niereninsuffizienz - Dialyse - Hyperparathyreoi dismus - Kalzimimetika - Kalzium-Phosphat-Produkt - Parat hormon - Vitamin D

Keywords

Calcimimetics - calcium-phosphorus product - chronic kidney disease - dialysis - hyperparathyroidism - parathyroid hor mone - vitamin D

• Literatur

• 1 Almaden Y, Hernandez A, Torregrosa V. et al. High phosphate level directly stimulates parathyroid hormone secretion and synthesis by human parathyroid tissue in vitro. J Am Soc Nephrol 1998; 09: 1845-1852.
• 2 Block GA. Calcium, calcimimetics and clinical outcomes. Clin J Am Soc Nephrol 2006; 01: 170-171.
• 3 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: 607-617.
• 4 Block GA, Klassen PS, Lazarus JM. et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 2004; 15: 2208-2218.
• 5 Block GA, Martin KJ, de Francisco ALM. et al. Cinacalcet hydrochloride for secondary hyper parathyroidism in patients receiving hemodialysis. N Engl J Med 2004; 350: 1516-1525.
• 6 Block GA, Zeig S, Sugihara J. et al. for the TAR-GET Investigators. Combined therapy with cinacalcet and low doses of vitamin D sterols in patients with moderate to severe secondary hyper parathyroidism. Nephrol Dial Transplant. 2008 Feb 28 [Epub ahead of print].
• 7 Brown EM. Calcium receptor and regulation of parathyroid hormone secretion. Rev Endocr Metab Disord 2000; 01: 307-315.
• 8 Brown EM. Extracellular Ca²⁺ sensing, regulation of parathyroid cell function, and role of Ca²⁺ and other ions as extracellular (first) messengers. Physiol Rev 1991; 71: 371-411.
• 9 Brown EM, Gamba G, Riccardi D. et al. Cloning and characterization of an extracellular Ca²⁺-sensing receptor from bovine parathyroid. Nature 1993; 366: 575-580.
• 10 Brown EM, Pollak M, Seidman CE. et al. Calciumion-sensing cell-surface receptors. N Engl J Med 1995; 333: 234-240.
• 11 Bushinsky DA. The contribution of metabolic acidosis to renal osteodystrophy. Kidney Int 1995; 47: 1816-1832.
• 12 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: 58-67.
• 13 Chertow GM, Blumenthal S, Turner S. et al. on behalf of the CONTROL Investigators. 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; 01: 305-312.
• 14 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; 02: 898-905.
• 15 Coburn JW, Maung HM. Calcimimetic agents and the calcium-sensing receptor. Curr Opin Nephrol Hypertens 2000; 09: 123-132.
• 16 Coen G, Calabria S, Bellinghieri G. et al. Parathy roidectomy in chronic renal failure: Short- and long-term results on parathyroid function, blood pressure and anemia. Nephron 2001; 88: 149-155.
• 17 Coyne DW, Stegman MH, Azad H. et al. Cinacalcet HCl controls secondary hyperparathyroidism regardless of gender, race, age, and geography in patients with chronic kidney disease receiving dialysis. J Am Soc Nephrol 2003; 14: 464A (SA-PO754).
• 18 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: 1793-1800.
• 19 Drüeke TB. Calcimimetics versus vitamin D: What are their relative roles?. Blood Purif 2004; 22: 38-43.
• 20 Drüeke TB. Treatment of secondary hyper parathyroidism with vitamin D derivatives and calcimimetics before and after start of dialysis. Nephrol Dial Transplant 2002; 17 (Suppl. 11) 20-22.
• 21 Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol 2005; 289: 8-28.
• 22 Dusso AS, Pavlopoulos T, Naumovich L. et al. p21 (WAF1) and transforming growth factor-alpha mediate dietary phosphate regulation of parathyroid cell growth. Kidney Int 2001; 59: 855-865.
• 23 Elder G. Pathophysiology and recent advances in the management of renal osteodystrophy. J Bone Miner Res 2002; 17: 2094-2105.
• 24 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: 1048-1053.
• 25 Garabedian M, Holick MF, Deluca HF, Boyle IT. Control of 25-hydroxycholecalciferol metabolism by parathyroid glands. Proc Natl Acad Sci USA 1972; 69: 1673-1676.
• 26 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: 1017-1024.
• 27 Goodman WG, Turner SA. Future role of calcimimetics in end-stage renal disease. Adv Ren Replace Ther 2002; 09: 200-208.
• 28 Ix JH, Quarles LD, Chertow GM. Guidelines for disorders of mineral metabolism and secondary hyperparathyroidism should not yet be modified. Nature Clin Pract Nephrol 2006; 02: 337-339.
• 29 Jean G, Chazot C, Charra B. 12 months cinacalcet therapy in hemodialysis patients with secondary hyperparathyroidism: effect on bone markers. Clin Nephrol 2007; 68: 63-64.
• 30 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: 397-411.
• 31 Lien YH, Silva AL, Whittman D. Effects of cinacalcet on bone mineral density in patients with secondary hyperparathyroidism. Nephrol Dial Transplant 2005; 20: 1232-1237.
• 32 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: 800-807.
• 33 Llach F. Hyperphosphatemia in end-stage renal disease patients: pathophysiological consequences. Kidney Int 1999; 56 (Suppl. 73) S31-S37.
• 34 Locatelli F, Cannata-Andia JB, Drüeke TB. et al. Management of disturbances of calcium and phosphate metabolism in chronic renal insufficiency, with emphasis on the control of hyper phosphataemia. Nephrol Dial Transplant 2002; 17: 723-731.
• 35 Lomonte C, Antonelli M, Losurdo N. et al. Cinacalcet is effective in relapses of secondary hyper parathyroidism after parathyroidectomy. Nephrol Dial Transplant 2007; 22: 2056-2062.
• 36 Malluche HH, Monier-Faugere MC, Wang G. et al. An assessment of cinacalcet HCl effects on bone histology in dialysis patients with secondary hy perparathyroidism. Clin Nephrol 2008; 69: 269-278.
• 37 Martin KJ, Jüppner H, Sherrard DJ. et al. First- and second-generation immunometric PTH assays during treatment of hyperparathyroidism with cinacalcet HCl. Kidney Int 2005; 68: 1236-1243.
• 38 Messa P, Alberti L, Como G. et al. Calcimimetic increases osteoprotegerin and decreases fetuin-A levels in dialysis patients. Nephrol Dial Transplant 2007; 22: 2724-2725.
• 39 Messa P, Macario F, Yagoob M. et al. The OPTIMA study: assessing a new cinacalcet (Sensipar/Mimpara) treatment algorithm for secondary hyper parathyroidism. Clin J Am Soc Nephrol 2008; 03: 36-45.
• 40 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: 760-771.
• 41 Moe SM, Cunningham J, Bommer J. et al. Long term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl. Nephrol Dial Transplant 2005; 20: 2186-2193.
• 42 Monge M, Shahapuni I, Oprisiu R. et al. Reappraisal of 2003 NKF-K/DOQI guidelines for management of hyperparathyroidism in chronic kidney disease patients. Nature Clin Pract Nephrol 2006; 02: 326-336.
• 43 Nakagawa K, Perez EC, Oh J. et al. Cinacalcet does not affect longitudinal growth but increases body weight gain in experimental uraemia. Nephrol Dial Transplant. 2008 Apr 11 [Epub ahead of print].
• 44 National Kidney Foundation: K/DOQI clinical practice guidelines: bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003; 42 (Suppl. 04) S1-S201.
• 45 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: 959-967.
• 46 Padhi D, Harris R, Salfi M. et al. Cinacalcet HCl absorption is not affected by coadministration of medications commonly prescribed to chronic kidney disease (pantoprazole sodium, sevelamer HCl, and calcium carbonate). J Am Soc Nephrol 2003; 14: 461A (SA-PO744).
• 47 Padhi D, Salfi M, Harris RZ. The pharmacokinetics of cinacalcet are unaffected following consumption of high- and low-fat meals. Am J Ther 2007; 14: 235-240.
• 48 Padhi D, Sullivan JT. Cinacalcet does not affect the pharmacokinetics or pharmacodynamics of warfarin. Drugs R&D 2007; 08: 79-87.
• 49 Sensipar™ . Medical description-Issue Date 03/08/2004. Amgen Inc. Thousand Oaks, CA. 91320-1799 USA.
• 50 Shahapuni I, Monge M, Oprisiu R. et al. Drug Insight: renal indications of calcimimetics. Nature Clin Pract Nephrol 2006; 02: 316-325.
• 51 Silverstein DM, Kher KK, Moudgil A. et al. Cinacalcet is efficacious in pediatric dialysis patients. Pediatr Nephrol. 2008 Feb21 [Epub ahead of print].
• 52 Slatopolsky E, Brown A, Dusso A. Pathogenesis of secondary hyperparathyroidism. Kidney Int 1999; 56 (Suppl. 73) S14-S19.
• 53 Srinivas TR, Schold JD, Womer KL. et al. Improvement of hypercalcemia with cinacalcet after kidney transplantation. Clin J Am Soc Nephrol 2006; 01: 323-326.
• 54 Urena P, Frazao JM. Calcimimetic agents: Review and perspectives. Kidney Int 2003; 63 su85: S91-S96.
• 55 Wada M, Nagano N. Control of parathyroid cell growth by calcimimetics. Nephrol Dial Transplant 2003; 18 (Suppl. 03) iii13-iii17.
• 56 Wüthrich RP, Martin D, Bilezikian JP. The role of calcimimetics in the treatment of hyperparathy roidism. Eur J Clin Invest 2007; 37: 915-922.