Background/Aims: Oxidative stress is one of the leading factors contributing to increased mortality in patients with chronic kidney disease (CKD) and secondary hyperparathyroidism (sHPT). Cinacalcet is now commonly used in the treatment of sHPT in patients with CKD. The aim of this study was to assess the influence of treatment with cinacalcet on the oxidative stress markers in patients on hemodialysis with sHPT. Methods: In 58 hemodialysed patients with sHPT (parathyroid hormone [PTH] > 300 pg/mL) plasma Advanced Oxidation Protein Products (AOPP), serum total antioxidant capacity – ImAnOx (TAS/TAC), serum PTH, calcium and phosphate concentrations were assessed before the first dose of cinacalcet and after 6 months of treatment. Results: Serum PTH concentration decreased significantly from 895 (748–1,070) to 384 (289–510) pg/mL after 6 months of treatment; p < 0.0001. Mean serum concentrations of -calcium and phosphate remained stable. Plasma AOPP concentration decreased significantly from 152 (126–185) to 49 -(43–57) µmol/L after 6 months of treatment; p < 0.0001. ImAnOx significantly increased from 260 (251–270) to 272 (264–280) µmol/L; p = 0.04. After 6 months of treatment, a significant, positive correlation was found between ImAnOx and the daily dose of cinacalcet (r = 0.30; p = 0.02). Also, the change of serum ImAnOx during treatment with cinacalcet significantly correlated with the daily dose of cinacalcet r = 0.35; p = 0.01. No significant correlations were found between plasma AOPP concentration or ImAnOx and PTH, or their changes in time. Conclusions: (1) Six-month treatment based on cinacalcet seems to reduce oxidative stress markers in maintenance hemodialysis patients with sHPT. (2) This benefit may be related rather to the direct action of cinacalcet than to the serum PTH concentration decrease.

Keywords:
Cinacalcet, Hemodialysis, Oxidative stress, Secondary hyperparathyroidism
1.
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351: 1296–305.
2.
Locatelli F, Marcelli D, Conte F, D'Amico M, Del Vecchio L, Limido A, Malberti F, Spotti D: Cardiovascular disease in chronic renal failure: the challenge continues. Registro Lombardo Dialisi e Trapianto. Nephrol Dial Transplant 2000; 15: 69–80.
3.
Chronic Kidney Disease Prognosis Consortium, Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, Coresh J, Gansevoort RT: Association of -estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010; 375: 2073–2081.
4.
Del Vecchio L, Locatelli F, Carini M: What we know about oxidative stress in patients with chronic kidney disease on dialysis – clinical effects, potential treatment, and prevention. Semin Dial 2011; 24: 56–64.
5.
Elahi MM, Kong YX, Matata BM: Oxidative stress as a mediator of cardiovascular disease. Oxid Med Cell Longev 2009; 2: 259–269.
6.
Nagano N: Pharmacological and clinical properties of calcimimetics: calcium receptor activators that afford an innovative approach to controlling hyperparathyroidism. Pharmacol Ther 2006; 109: 339–365.
7.
Kameda T, Mano H, Yamada Y, et al: Calcium-sensing receptor in mature osteoclasts, which are bone resorbing cells. Biochem Biophys Res Commun 1998; 245: 419–422.
8.
Weston AH, Absi M, Ward DT, et al: Evidence in favor of a calcium-sensing receptor in arterial endothelial cells: studies with calindol and calhex 231. Circ Res 2005; 97: 391–398.
9.
Smajilovic S, Hansen JL, Christoffersen TE, et al: Extracellular calcium sensing in rat aortic vascular smooth muscle cells. Biochem Biophys Res Commun 2006; 348: 1215–1223.
10.
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: 946–955.
11.
Ceglia L, Harris SS, Rasmussen HM, Dawson-Hughes B: Activation of the calcium sensing receptor stimulates gastrin and gastric acid secretion in healthy participants. Osteoporos Int 2009; 20: 71–78.
12.
Gray E, Muller D, Squires PE, et al: Activation of the extracellular calcium-sensing receptor initiates insulin secretion from human islets of Langerhans: involvement of protein kinases. J Endocrinol 2006; 190: 703–710.
13.
Cifuentes M, Albala C, Rojas C: Calcium-sensing receptor expression in human adipocytes. Endocrinology 2005; 146: 2176–2179.
14.
Marie PJ: The calcium-sensing receptor in bone cells: a potential therapeutic target in osteoporosis. Bone 2010; 46: 571–576.
15.
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: 1327–1339.
16.
Fishbane S, Shapiro WB, Corry DB, et al: Cinacalcet HCl 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: 1718–1725.
17.
Kuczera P, Adamczak M, Więcek A: Safety and efficiency of treatment with cinacalcet of haemodialysed patients with chronic kidney disease and secondary hyperparathyroidism. Endokrynol Pol 2013; 64: 176–181.
18.
Bellasi A, Reiner M, Pétavy F, et al: Presence of valvular calcification predicts the response to cinacalcet: data from the ADVANCE study. J Heart Valve Dis 2013; 22: 391–399.
19.
Kuczera P, Adamczak M, Machnik G, Okopien B, Wiecek A: Treatment with cinacalcet increases plasma adiponectin concentration in hemodialyzed patients with chronic kidney disease and secondary hyperparathyroidism. Endocr Pract 2015; 21: 743–749.
20.
Kolonko A, Chudek J, Szotowska M, Kuczera P, Wiecek A: Cardiovascular risk factors and markers of atherosclerosis in stable kidney transplant recipients. Transplant Proc 2016; 48: 1543–1550.
21.
Gonzalez E, Bajo MA, Carrero JJ, et al: An increase of plasma advanced oxidation protein products levels is associated with cardiovascular risk in incident peritoneal dialysis patients: a pilot study. Oxid Med Cell Longev 2015; 2015: 219569.
22.
Eiselt J, Rajdl D, Racek J, Vostrý M, Rulcová K, Wirth J: Asymmetric dimethylarginine and progression of chronic kidney disease: a one-year follow-up study. Kidney Blood Press Res 2014; 39: 50–57.
23.
Kim HJ, Sato T, Rodríguez-Iturbe B, Vaziri ND: Role of intrarenal angiotensin system activation, oxidative stress, inflammation, and impaired nuclear factor-erythroid-2-related factor 2 activity in the progression of focal glomerulosclerosis. J Pharmacol Exp Ther 2011; 337: 583–590.
24.
Duni A, Liakopoulos V, Rapsomanikis KP, Dounousi E: Chronic kidney disease and disproportionally increased cardiovascular damage: does oxidative stress explain the burden? Oxid Med Cell Longev 2017; 2017: 9036450.
25.
Liakopoulos V, Roumeliotis S, Gorny X, Dounousi E, Mertens PR: Oxidative Stress in hemodialysis patients: a review of the literature. Oxid Med Cell Longev 2017; 2017: 3081856.
26.
Ortiz-Capisano MC, Ortiz PA, Garvin JL, Harding P, Beierwaltes WH: Expression and function of the calcium-sensing receptor in juxtaglomerular cells. Hypertension 2007; 50: 737–743.
27.
Ortiz-Capisano MC, Reddy M, Mendez M, Garvin JL, Beierwaltes WH: Juxtaglomerular cell CaSR stimulation decreases renin release via activation of the PLC/IP(3) pathway and the ryanodine receptor. Am J Physiol Renal Physiol 2013; 304:F248–F256.
28.
Atchison DK, Ortiz-Capisano MC, Beierwaltes WH: Acute activation of the calcium-sensing receptor inhibits plasma renin activity in vivo. Am J Physiol Regul Integr Comp Physiol 2010; 299:R1020–R1026.
29.
Touyz RM: Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: what is the clinical significance? Hypertension 2004; 44: 248–252.
30.
Kuczera P, Adamczak M, Wiecek A: Treatment with cinacalcet decreases systolic blood pressure in haemodialysed patients with chronic kidney disease and secondary hyperparathyroidism. Arterial Hypertens 2015; 19: 129–134.
31.
Chang TI, Abdalla S, London GM, Block GA, Correa-Rotter R, Drüeke TB, Floege J, Herzog CA, Mahaffey KW, Moe SM, Parfrey PS, Wheeler DC, Dehmel B, Goodman WG, Chertow GM: The effects of cinacalcet on blood pressure, mortality and cardiovascular endpoints in the EVOLVE trial. J Hum Hypertens 2016; 30: 204–209.
32.
Koizumi M, Komaba H, Nakanishi S, Fujimori A, Fukagawa M: Cinacalcet treatment and serum FGF23 levels in haemodialysis patients with secondary hyperparathyroidism. Nephrol Dial Transplant 2012; 27: 784–790.
33.
Kuczera P, Adamczak M, Wiecek A: Cinacalcet treatment decreases plasma fibroblast growth factor 23 concentration in haemodialysed patients with chronic kidney disease and secondary hyperparathyroidism. Clin Endocrinol (Oxf) 2014; 80: 607–612.
34.
Richter B, Haller J, Haffner D, Leifheit-Nestler M: Klotho modulates FGF23-mediated NO synthesis and oxidative stress in human coronary artery endothelial cells. Pflugers Arch 2016; 468: 1621–1635.
35.
Ari E, Kaya Y, Demir H, Asicioglu E, Eren Z, Celik E, Arikan H: Cinacalcet may improve oxidative DNA damage in maintenance hemodialysis patients: an observational study. Int Urol Nephrol 2014; 46: 1843–1849.
36.
Choi SR, Lim JH, Kim MY, Hong YA, Chung BH, Chung S, Choi BS, Yang CW, Kim YS, Chang YS, Park CW: Cinacalcet improves endothelial dysfunction and cardiac hypertrophy in patients on hemodialysis with secondary hyperparathyroidism. Nephron Clin Pract 2012; 122: 1–8.
37.
Lu L, Erhard P, Salomon RG, Weiss MF: Serum vitamin E and oxidative protein modification in hemodialysis: a randomized clinical trial. Am J Kidney Dis 2007; 50: 305–313.
38.
Diepeveen SH, Verhoeven GW, Van Der Palen J, et al: Effects of atorvastatin and vitamin E on lipoproteins and oxidative stress in dialysis patients: a randomised-controlled trial. J Intern Med 2005; 257: 438–445.
39.
Ando M, Sanaka T, Nihei H: Eicosapentanoic acid reduces plasma levels of remnant lipoproteins and prevents in vivo peroxidation of LDL in dialysis patients. J Am Soc Nephrol 1999; 10: 2177–2184.
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2018
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