The influence of vitamin D analogs on calcification modulators, N-terminal pro-B-type natriuretic peptide and inflammatory markers in hemodialysis patients: a randomized crossover study

Ditte Hansen, Knud Rasmussen, Lars M Rasmussen, Helle Bruunsgaard, Lisbet Brandi, Ditte Hansen, Knud Rasmussen, Lars M Rasmussen, Helle Bruunsgaard, Lisbet Brandi

Abstract

Background: The risk of cardiovascular disease is tremendously high in dialysis patients. Dialysis patients treated with vitamin D analogs show decreased cardiovascular morbidity and mortality compared with untreated patients. We examined the influence of two common vitamin D analogs, alfacalcidol and paricalcitol, on important cardiovascular biomarkers in hemodialysis patients. Anti-inflammatory effects and the influence on regulators of vascular calcification as well as markers of heart failure were examined.

Methods: In 57 chronic hemodialysis patients enrolled in a randomized crossover trial comparing paricalcitol and alfacalcidol, we examined the changes in osteoprotegerin, fetuin-A, NT-proBNP, hs-Crp, IL-6 and TNF-α, during 16 weeks of treatment.

Results: NT-proBNP and osteoprotegerin increased comparably in the paricalcitol and alfacalcidol-treated groups. Fetuin-A increased significantly in the alfacalcidol-treated group compared with the paricalcitol-treated group (difference 32.84 μmol/l (95% C.I.; range 0.21-67.47)) during the first treatment period. No difference was found between the groups during the second treatment period, and IL-6, TNF-α and hs-Crp were unchanged in both treatment groups.

Conclusions: Paricalcitol and alfacalcidol modulate regulators of vascular calcification. Alfacalcidol may increase the level of the calcification inhibitor fetuin-A. We did not find any anti-inflammatory effect or difference in changes of NT-proBNP.

Trial registry: ClinicalTrials.gov NCT00469599 May 3 2007.

Figures

Figure 1
Figure 1
Patients flow diagram.
Figure 2
Figure 2
Changes in log fetuin-A according to changes in hs-Crp. Univariate analysis of changes in log fetuin-A as an independent variable versus changes in hs-Crp during 16 weeks of treatment with paricalcitol and alfacalcidol.
Figure 3
Figure 3
Changes in osteoprotegerin according to changes in parathyroid hormone. Univariate analysis of changes in osteoprotegerin as an independent variable versus changes in parathyroid hormone during 16 weeks of treatment with paricalcitol and alfacalcidol.

References

    1. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis. 1998;32:S112–S119.
    1. Pilz S, Tomaschitz A, Friedl C, Amrein K, Drechsler C, Ritz E, Boehm BO, Grammer TB, Marz W. Vitamin D status and mortality in chronic kidney disease. Nephrol Dial Transplant. 2011;26:3603–3609.
    1. Wolf M, Shah A, Gutierrez O, Ankers E, Monroy M, Tamez H, Steele D, Chang Y, Camargo CA Jr, Tonelli M, Thadhani R. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int. 2007;72:1004–1013.
    1. Drechsler C, Pilz S, Obermayer-Pietsch B, Verduijn M, Tomaschitz A, Krane V, Espe K, Dekker F, Brandenburg V, Marz W, Ritz E, Wanner C. Vitamin D deficiency is associated with sudden cardiac death, combined cardiovascular events, and mortality in haemodialysis patients. Eur Heart J. 2010;31:2253–2261.
    1. Drechsler C, Verduijn M, Pilz S, Dekker FW, Krediet RT, Ritz E, Wanner C, Boeschoten EW, Brandenburg V. Vitamin D status and clinical outcomes in incident dialysis patients: results from the NECOSAD study. Nephrol Dial Transplant. 2011;26:1024–1032.
    1. Teng M, Wolf M, Ofsthun MN, Lazarus JM, Hernan MA, Camargo CA Jr, Thadhani R. Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol. 2005;16:1115–1125.
    1. Tentori F, Albert JM, Young EW, Blayney MJ, Robinson BM, Pisoni RL, Akiba T, Greenwood RN, Kimata N, Levin NW, Piera LM, Saran R, Wolfe RA, Port FK. The survival advantage for haemodialysis patients taking vitamin D is questioned: findings from the Dialysis Outcomes and Practice Patterns Study. Nephrol Dial Transplant. 2008;24:963–972.
    1. Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med. 2003;349:446–456.
    1. Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C. Vitamin D: modulator of the immune system. Curr Opin Pharmacol. 2010;10:482–496.
    1. Raggi P, Giachelli C, Bellasi A. Interaction of vascular and bone disease in patients with normal renal function and patients undergoing dialysis. Nat Clin Pract Cardiovasc Med. 2007;4:26–33.
    1. Ketteler M, Schlieper G, Floege J. Calcification and cardiovascular health: new insights into an old phenomenon. Hypertension. 2006;47:1027–1034.
    1. Bodyak N, Ayus JC, Achinger S, Shivalingappa V, Ke Q, Chen YS, Rigor DL, Stillman I, Tamez H, Kroeger PE, Wu-Wong RR, Karumanchi SA, Thadhani R, Kang PM. Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals. Proc Natl Acad Sci U S A. 2007;104:16810–16815.
    1. Kong J, Kim GH, Wei M, Sun T, Li G, Liu SQ, Li X, Bhan I, Zhao Q, Thadhani R, Li YC. Therapeutic effects of vitamin D analogs on cardiac hypertrophy in spontaneously hypertensive rats. Am J Pathol. 2010;177:622–631.
    1. Tamez H, Zoccali C, Packham D, Wenger J, Bhan I, Appelbaum E, Pritchett Y, Chang Y, Agarwal R, Wanner C, Lloyd-Jones D, Cannata J, Thompson BT, Andress D, Zhang W, Singh B, Zehnder D, Pachika A, Manning WJ, Shah A, Solomon SD, Thadhani R. Vitamin D reduces left atrial volume in patients with left ventricular hypertrophy and chronic kidney disease. Am Heart J. 2012;164:902–909.
    1. Hansen D, Brandi L, Rasmussen K. Treatment of secondary hyperparathyroidism in haemodialysis patients: a randomised clinical trial comparing paricalcitol and alfacalcidol. BMC Nephrol. 2009;10:28.
    1. Hansen D, Rasmussen K, Danielsen H, Meyer-Hofmann H, Bacevicius E, Lauridsen TG, Madsen JK, Tougaard BG, Marckmann P, Thye-Roenn P, Nielsen JE, Kreiner S, Brandi L. No difference between alfacalcidol and paricalcitol in the treatment of secondary hyperparathyroidism in hemodialysis patients: a randomized crossover trial. Kidney Int. 2011;8:841–850.
    1. Reinhard H, Lajer M, Gall MA, Tarnow L, Parving HH, Rasmussen LM, Rossing P. Osteoprotegerin and mortality in type 2 diabetic patients. Diabetes Care. 2010;33:2561–2566.
    1. Jorsal A, Tarnow L, Flyvbjerg A, Parving HH, Rossing P, Rasmussen LM. Plasma osteoprotegerin levels predict cardiovascular and all-cause mortality and deterioration of kidney function in type 1 diabetic patients with nephropathy. Diabetologia. 2008;51:2100–2107.
    1. Altman DG. Practical Statistics for Medical Research. 1. Boca Raton: Chapmann & Hall/CRC; 1991.
    1. Hansen D, Rasmussen K, Pedersen SM, Rasmussen LM, Brandi L. Changes in fibroblast growth factor 23 during treatment of secondary hyperparathyroidism with alfacalcidol or paricalcitol. Nephrol Dial Transplant. 2012;27:2263–2269.
    1. Matsui I, Hamano T, Mikami S, Fujii N, Takabatake Y, Nagasawa Y, Kawada N, Ito T, Rakugi H, Imai E, Isaka Y. Fully phosphorylated fetuin-A forms a mineral complex in the serum of rats with adenine-induced renal failure. Kidney Int. 2009;75:915–928.
    1. Schlieper G, Westenfeld R, Brandenburg V, Ketteler M. Inhibitors of calcification in blood and urine. Semin Dial. 2007;20:113–121.
    1. Chen HY, Chiu YL, Hsu SP, Pai MF, Yang JY, Peng YS. Low serum fetuin A levels and incident stroke in patients with maintenance haemodialysis. Eur J Clin Invest. 2013;43:387–396.
    1. Hermans MM, Brandenburg V, Ketteler M, Kooman JP, van der Sande FM, Boeschoten EW, Leunissen KM, Krediet RT, Dekker FW. Association of serum fetuin-A levels with mortality in dialysis patients. Kidney Int. 2007;72:202–207.
    1. Ketteler M, Bongartz P, Westenfeld R, Wildberger JE, Mahnken AH, Bohm R, Metzger T, Wanner C, Jahnen-Dechent W, Floege J. Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet. 2003;361:827–833.
    1. Lebreton JP, Joisel F, Raoult JP, Lannuzel B, Rogez JP, Humbert G. Serum concentration of human alpha 2 HS glycoprotein during the inflammatory process: evidence that alpha 2 HS glycoprotein is a negative acute-phase reactant. J Clin Invest. 1979;64:1118–1129.
    1. Wang AY, Woo J, Lam CW, Wang M, Chan IH, Gao P, Lui SF, Li PK, Sanderson JE. Associations of serum fetuin-A with malnutrition, inflammation, atherosclerosis and valvular calcification syndrome and outcome in peritoneal dialysis patients. Nephrol Dial Transplant. 2005;20:1676–1685.
    1. Manenti L, Vaglio A, Pasquali S. Increased fetuin-A levels following treatment with a vitamin D analog. Kidney Int. 2010;78:1187–1189.
    1. Ix JH, Wassel CL, Kanaya AM, Vittinghoff E, Johnson KC, Koster A, Cauley JA, Harris TB, Cummings SR, Shlipak MG. Fetuin-A and incident diabetes mellitus in older persons. JAMA. 2008;300:182–188.
    1. Jensen MK, Bartz TM, Mukamal KJ, Djousse L, Kizer JR, Tracy RP, Zieman SJ, Rimm EB, Siscovick DS, Shlipak M, Ix JH. Fetuin-A, type 2 diabetes, and risk of cardiovascular disease in older adults: the cardiovascular health study. Diabetes Care. 2013;36:1222–1228.
    1. Kazama JJ, Omori K, Takahashi N, Ito Y, Maruyama H, Narita I, Gejyo F, Iwasaki Y, Fukagawa M. Maxacalcitol therapy decreases circulating osteoprotegerin levels in dialysis patients with secondary hyperparathyroidism. Clin Nephrol. 2005;64:64–68.
    1. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997;89:309–319.
    1. Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998;12:1260–1268.
    1. Price PA, June HH, Buckley JR, Williamson MK. Osteoprotegerin inhibits artery calcification induced by warfarin and by vitamin D. Arterioscler Thromb Vasc Biol. 2001;21:1610–1616.
    1. Nitta K, Akiba T, Uchida K, Kawashima A, Yumura W, Kabaya T, Nihei H. The progression of vascular calcification and serum osteoprotegerin levels in patients on long-term hemodialysis. Am J Kidney Dis. 2003;42:303–309.
    1. Nitta K, Akiba T, Uchida K, Otsubo S, Takei T, Yumura W, Kabaya T, Nihei H. Serum osteoprotegerin levels and the extent of vascular calcification in haemodialysis patients. Nephrol Dial Transplant. 2004;19:1886–1889.
    1. Ozkok A, Caliskan Y, Sakaci T, Erten G, Karahan G, Ozel A, Unsal A, Yildiz A. Osteoprotegerin/RANKL axis and progression of coronary artery calcification in hemodialysis patients. Clin J Am Soc Nephrol. 2012;7:965–973.
    1. Koo HM, Do HM, Kim EJ, Lee MJ, Shin DH, Kim SJ, Oh HJ, Yoo DE, Kim JK, Park JT, Han SH, Kang SW, Choi KH, Yoo TH. Elevated osteoprotegerin is associated with inflammation, malnutrition and new onset cardiovascular events in peritoneal dialysis patients. Atherosclerosis. 2011;219:925–930.
    1. Morena M, Terrier N, Jaussent I, Leray-Moragues H, Chalabi L, Rivory JP, Maurice F, Delcourt C, Cristol JP, Canaud B, Dupuy AM. Plasma osteoprotegerin is associated with mortality in hemodialysis patients. J Am Soc Nephrol. 2006;17:262–270.
    1. Parfrey PS, Foley RN, Harnett JD, Kent GM, Murray DC, Barre PE. Outcome and risk factors for left ventricular disorders in chronic uraemia. Nephrol Dial Transplant. 1996;11:1277–1285.
    1. Madsen LH, Ladefoged S, Corell P, Schou M, Hildebrandt PR, Atar D. N-terminal pro brain natriuretic peptide predicts mortality in patients with end-stage renal disease in hemodialysis. Kidney Int. 2007;71:548–554.
    1. Naganuma T, Sugimura K, Wada S, Yasumoto R, Sugimura T, Masuda C, Uchida J, Nakatani T. The prognostic role of brain natriuretic peptides in hemodialysis patients. Am J Nephrol. 2002;22:437–444.
    1. Thadhani R, Appelbaum E, Pritchett Y, Chang Y, Wenger J, Tamez H, Bhan I, Agarwal R, Zoccali C, Wanner C, Lloyd-Jones D, Cannata J, Thompson BT, Andress D, Zhang W, Packham D, Singh B, Zehnder D, Shah A, Pachika A, Manning WJ, Solomon SD. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial. JAMA. 2012;307:674–684.
    1. Wang AY, Fang F, Chan J, Wen YY, Qing S, Chan IH, Lo G, Lai KN, Lo WK, Lam CW, Yu CM. Effect of Paricalcitol on Left Ventricular Mass and Function in CKD--The OPERA Trial. J Am Soc Nephrol. 2013;25:175–186.
    1. van Ballegooijen AJ, Visser M, Kestenbaum B, Siscovick DS, de Boer IH, Gottdiener JS, deFilippi CR, Brouwer IA. Relation of vitamin D and parathyroid hormone to cardiac biomarkers and to left ventricular mass (from the Cardiovascular Health Study) Am J Cardiol. 2013;111:418–424.
    1. Tastan I, Schreckenberg R, Mufti S, Abdallah Y, Piper HM, Schluter KD. Parathyroid hormone improves contractile performance of adult rat ventricular cardiomyocytes at low concentrations in a non-acute way. Cardiovasc Res. 2009;82:77–83.
    1. Larsson T, Nisbeth U, Ljunggren O, Juppner H, Jonsson KB. Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int. 2003;64:2272–2279.
    1. Gutierrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, Smith K, Lee H, Thadhani R, Juppner H, Wolf M. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008;359:584–592.
    1. Wolf M, Molnar MZ, Amaral AP, Czira ME, Rudas A. Elevated Fibroblast growth factor 23 is a risk factor for kidney transplant loss and mortality. J Am Soc Nephrol. 2011;22:956–966.
    1. Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, Gutierrez OM, Aguillon-Prada R, Lincoln J, Hare JM, Mundel P, Morales A, Scialla J, Fischer M, Soliman EZ, Chen J, Go AS, Rosas SE, Nessel L, Townsend RR, Feldman HI, St John SM, Ojo A, Gadegbeku C, Di Marco GS, Reuter S, Kentrup D, Tiemann K, Brand M, Hill JA. et al.FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121:4393–4408.
    1. Kalantar-Zadeh K, Block G, Humphreys MH, Kopple JD. Reverse epidemiology of cardiovascular risk factors in maintenance dialysis patients. Kidney Int. 2003;63:793–808.
    1. Eleftheriadis T, Antoniadi G, Liakopoulos V, Kartsios C, Stefanidis I, Galaktidou G. Paricalcitol reduces basal and lipopolysaccharide-induced (LPS) TNF-alpha and IL-8 production by human peripheral blood mononuclear cells. Int Urol Nephrol. 2010;42:181–185.
    1. Alborzi P, Patel NA, Peterson C, Bills JE, Bekele DM, Bunaye Z, Light RP, Agarwal R. Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized double-blind pilot trial. Hypertension. 2008;52:249–255.
    1. Navarro-Gonzalez JF, Donate-Correa J, Mendez ML, de Fuentes MM, Garcia-Perez J, Mora-Fernandez C. Anti-inflammatory profile of paricalcitol in hemodialysis patients: a prospective, open-label, pilot study. J Clin Pharmacol. 2013;53:421–426.
    1. Izquierdo MJ, Cavia M, Muniz P, de Francisco AL, Arias M, Santos J, Abaigar P. Paricalcitol reduces oxidative stress and inflammation in hemodialysis patients. BMC Nephrol. 2012;13:159.
    1. Moe SM, Zekonis M, Harezlak J, Ambrosius WT, Gassensmith CM, Murphy CL, Russell RR, Batiuk TD. A placebo-controlled trial to evaluate immunomodulatory effects of paricalcitol. Am J Kidney Dis. 2001;38:792–802.
    1. Marckmann P, Agerskov H, Thineshkumar S, Bladbjerg EM, Sidelmann JJ, Jespersen J, Nybo M, Rasmussen LM, Hansen D, Scholze A. Randomized controlled trial of cholecalciferol supplementation in chronic kidney disease patients with hypovitaminosis D. Nephrol Dial Transplant. 2012;27:3523–3531.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit