Cardiovascular Calcification in Chronic Hemodialysis Patients: Contributors Interplay
Traditional cardiovascular risk factors are common among chronic kidney disease (CKD) patients. However the high prevalence of atherosclerosis and arterial calcification in CKD is far beyond the explanation by common cardiovascular risk factors. The aim of this study is to determine the incidence of cardiovascular calcification and its relation to demographic data, hemodialysis data and laboratory biomarkers and to evaluate the cardiovascular risk of atherosclerosis in hemodialysis patients. Fourty CKD patients on regular hemodialysis and twenty healthy volunteers were subjected to echocardiography, carotid ultrasound and laboratory studies including serum parathrmone (PTH), 25(OH) vitamin D, feutin and osteoprotegerin levels (OPG). The echocardiographic data showed a statistically significant increase in interventricular septum thickness (IVST), posterior wall thickness (PWT) and left ventricular mass index (LVMI) in patients group compared to the controls. Thirty patients (75%) had valvular calcification. There was significant increase in carotid intima-media thickness (CIMT) in patients group. Serum levels of Ph, PTH and Osteoprotegerin were significantly increased, however, serum levels of Ca, Vitamin D and Feutin were significantly decreased in patients group. Serum level of Ph, and Osteoprotogerin were significantly increased while Vitamin D and feutin were significantly decreased in patients with valvular calcification compared to patients without valvular calcifications. The level of Vitamin D and Fetuin were negatively correlated with creatinine, PTH and osteoprotogerin. While, the level of osteoprotogerin and PTH were positively correlated with creatinine and with each other, they were negatively correlated with HDL-c and eGFR. CIMT was positively correlated with LVMI, PWT, urea, creatinine, CRP, Ca and was negatively correlated with EF%, eGFR, HDL-c, vitamin D and Feutin. We concluded that hemodialysis patients with valvular calcifications were older in age, with a longer hemodialysis duration and showed higher Ph level, Ca x P product and OPG level and lower 25(OH)-vitamin D and fetuin A level. Also, they showed lower EF % and were on lower doses of alphacalcidol and higher doses of calcium compared to patients without valvular calcifications. So, our study points to the importance of administration of active vitamin D derivatives to decrease the risk of valvular calcification and atherosclerosis. Serum fetuin A and osteoprotegerin can be used as a simple, easily performed biomarkers mirroring valvular calcification in hemodialysis patients. Further studies should be done to assess trials for the addition of fetuin A in the treatment of CKD patients to prevent the occurrence of calcification.
Ashraf Abd El-Khalik Barakat,
Manar Abd El-Rouf Raafat Ameen,
Amna Ahmed Metwaly,
Fatma Mohammed Nasr,
Nevine Sherif Ali Khalil,
Cardiovascular Calcification in Chronic Hemodialysis Patients: Contributors Interplay, American Journal of Life Sciences.
Vol. 2, No. 5,
2014, pp. 251-259.
Tonelli M, Muntner P, Lloyd A, Manns BJ, Klarenbach S, Pannu N, James MT, Hemmelgarn BR ,2012: Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study. Lancet. 1;380(9844):807.
Longenecker JC, Coresh J, Powe NR, Levey AS, Fink NE, Martin A, Klag MJ. 2002: Traditional cardiovascular disease risk factors in dialysis patients compared with the general population: the CHOICE Study. J Am Soc Nephrol.;13:1918–1927.
Budoff MJ, Rader DJ, Reilly MP, Mohler ER, Lash J, Yang W, Rosen L, Glenn M, Teal V, Feldman HI.,2011: Relationship of estimated GFR and coronary artery calcification in the CRIC (Chronic Renal Insufficiency Cohort) Study. Am J Kidney Dis. ;58:519–526
London GM, Guérin AP, Marchais SJ, Métivier F, Pannier B, Adda H., 2003: Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant.;18:1731–1740.
Disthabanchong S., 2013: Lowering vascular calcification burden in chronic kidney disease: Is it possible? World J Nephrol. 6;2(3):55
Dellegrottaglie S, Sanz J, Rajagopalan S., 2006: Molecular determinantsof vascular calcification: A bench to bedside view. Curr Mol Med; 6: 5524.
Shanahan CM, Cary NR, Salisbury JR, Proudfoot D, Weissberg PL, Edmonds ME., 1999:,Medial localization of mineralizationregulating proteins in association with Mönckeberg’s sclerosis: Evidence for smooth muscle cell-mediated vascular calcification. Circulation; 100: 212176.
Vattikuti R, Towler DA., 2004: Osteogenic regulation of vascular calcification: An early perspective. Am J Physiol Endocrine Metab; 286: E6696.
Ikee R, Honda K, Oka M, Maesato K, Mano T, Moriya H, Ohtake T, Kobayashi S., 2008:Association of heart valve calcification with malnutrition-inflammation complex syndrome, betamicroglobulin, and carotid intima media thickness in patients on hemodialysis. Ther Apher Dial; 12: 4468.
Rochelle C , Corretti M & Henrich W., 2010:Valvular Heart Disease In Patients With End-Stage Renal Disease. J Am Soc Nephrol 20: 388–396.
Block GA, Spiegel DM, Ehrlich J, Mehta R, Lindbergh J, Dreisbach A, Raggi P., 2005: Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int; 68: 181824.
Cobble M and Bale B. , 2010:Carotid intima-media thickness: Knowledge and application to every day practice.; 122 (1): 28
Ossareh S, Alaei A and Saedi D., 2011: Carotid intima-media thickness in maintenance hemodialysis patients: role of cardiovascular risk factor.; 5 (3): 1174.
Francesco A B , Francesco M, Giovanni T and Carmine Z., 2001: Prognostic Value of Ultrasonographic Measurement of Carotid Intima Media Thickness in Dialysis Patients.J Am Soc Nephrol ; 12:242464.
Saritas T, Tascilar E, Abaci A, Yozgat Y, Dogan M, Dundaroz R, Hasimi A, Yesilkaya E, Lenk MK and Kilic A., 2010:Importance of plasma N-terminal pro B-type natriuretic peptide, epicardial adipose tissue, and carotid intima-media thicknesses in asymptomatic obese children. Pediatr Cardiol.; 31(6):79.
Lee CT, Tsai YC, Ng HY, Su Y, Lee WC, Lee LC, Chiou TT, Liao SC, Hsu KT., 2009: Association between C-reactive protein and biomarkers of bone and mineral metabolism in chronic hemodialysis patients: A cross-sectional study. J Ren Nutr; 19: 2227.
Wang AY, Lam CW, Wang M, Chan IH, Yu CM, Lui SF, Sanderson JE. 2008 Increased circulating inflammatory proteins predict a worse prognosis with valvular calcification in endstage renal disease: A prospective cohort study. Am J Nephrol; 28: 6653.
Chertow GM, Raggi P, Chasan-Taber S, Bommer J, Holzer H, Burke SK,. 2004: Determinants of progressive vascular calcification in haemodialysis patients. Nephrol Dial Transplant. ;19:1489 –1496.
Galassi A, Spiegel DM, Bellasi A, Block GA, Raggi P., 2006: Accelerated vascular calcification and relative hypoparathyroidism in incident haemodialysis diabetic patients receiving calcium binders. Nephrol Dial Transplant. ;21:3215–3222.
Leea,C, Chuab S, Hsuc C, Tsaia Y, 2013: Biomarkers associated with vascular and valvular calcification in chronic hemodialysis patients Disease Markers ; 34; 229–235
Davies MR, Lund RJ, Hruska KA:, 2003: BMP-7 is an efficacious treatment of vascular calcification in a murine model of atherosclerosis and chronic renal failure. J Am Soc Nephrol ; 14: 1559–1567.
Mizobuchi M, Finch JL, Martin DR, Slatopolsky E: 2007: Differential effects of vitamin D receptor activators on vascular calcification in uremic rats. Kidney Int ; 72: 709–715.
Schafer C, Heiss A, Schwarz A, Westenfeld R, Ketteler M, Floege J, Muller-Esterl W, Schinke T, Jahnen-Dechent W., 2003: The serum protein alpha Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J Clin Invest. ;14:357–366.
Reynolds JL, Skepper JN, McNair R, Kasama T, Gupta K, Weissberg PL, Jahnen-Dechent W, Shanahan CM., 2005: Multifunctional roles for serum protein fetuin-a in inhibition of human vascular smooth muscle cell calcification. J Am Soc Nephrol.;14:2920–2930
Ketteler M, Bongartz P, Westenfeld R, Wildberger JE, Mahnken AH, Bohm R, Metzger T, Wanner C, Jahnen-Dechent W, Floege J., 2003: Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet. ;14:827–833.
Pateinakis P, Papagianni A, Douma S, Efstratiadis G, and Memmos D., 2013: Associations of fetuin-A and osteoprotegerin with arterial stiffness and early atherosclerosis in chronic hemodialysis patients. BMC Nephrol. ; 14: 122.
Aoki A, Murata M, Asano T, Ikoma A, Sasaki M, Saito T, Otani T, Jinbo S, Ikeda N, Kawakami M, Ishikawa SE., 2013: Association of serum osteoprotegerin with vascular calcification in patients with type 2 diabetes. Cardiovas Diabetol.;14:11.
Speer G, Fekete BC, El Hadj Othmane T, Szabo T, Egresits J, Fodor E, Kiss I, Logan AG, Nemcsik J, Szabo A, Nemeth ZK, Szathmari M, Tisler A., 2008:Serum osteoprotegerin level, carotid-femoral pulse wave velocity and cardiovascular survival in haemodialysis patients. Nephrol Dial Transplant. ;14:3256–3262
Morena M, Terrier N, Jaussent I, Leray-Moragues H, Chalabi L, Rivory JP, Maurice F, Delcourt C, Cristol JP, Canaud B, Dupuy AM., 2006: Plasma osteoprotegerin is associated with mortality in hemodialysis patients. J Am Soc Nephrol. ;14:262–270
Gottdiener J.S. , Bendnarz I., Devereaux R., 2004:American Society of Echocardiography recommendations for use of echocardiography inclinical trials. Journal of American Society ofEchocardiography; ;17 : 1086 : 1119
Tsai YC, Lee CT, Huang TL, Cheng BC, Kuo CC, Su Y, Ng HY, Yang CC, Chuang FR, Liao SC., 2007: Inflammatory marker but not adipokine predicts mortality among long-term hemodialysis patients. Mediators Inflamm ; 19819895.
Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM ,2001:Arterial calcifications, arterial stiffness and cardiovascular risk in end-stage renal disease. Hypertension; 38: 9 942.
Wang AY, Wang M, Woo J, Lam CW, Li PK, Lui SF, Sanderson JE., 2003: Cardiac valve calcification as an important predictor for all-cause mortality and cardiovascular mortality in longterm peritoneal dialysis patients: A prospective study. J Am Soc Nephrol ; 14: 1168.
Ernesto U , Waqas A & Martin A., 2003: Valvular and Perivalvular Abnormalities in End-Stage Renal Disease . The American Journal of Medical Sciences; 325:2242.
Raggi P, Bommer J, Glenn M., 2004: Valvular Calcification in Hemodialysis Patients Randomized to Calcium-Based Phosphorus Binders or Sevelamer. J Heart Valve Dis ; 13: 1.
Moe M, Drueke T, Block A., 2009: KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention,and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder(CKD–MBD).kidney international ; 76 : 49.
Ribeiro S, Ramos A& Brandao A., 1998: Cardiac valve calcification in haemodialysis patients: Role of calcium-phosphate metabolism. Nephrol Dial Transplant. ; 13: 202040.
Raggi P, Boulay A, Chasan-Taber S,. 2008: Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease? J Am Coll Cardiol 2008; 39: 695–701.
Barasch E, Gottdiener J, Larsen E., 2006: Cardiovascular morbidity and mortality in community-dwelling elderly individuals with calcification of the fibrous skeleton of the base of the heart and aortosclerosis (The Cardiovascular Health Study). Am J Cardiol; 97:121286.
Masho Y and Shigematsu T., 2007: Arteriosclerosis and vascular calcification in chronic kidney disease (CKD) patients.Clin Calcium. 17(3):39.
Blacher J, Pannier B, Guerin AP, Marchais, SJ, Safar ME, London GM. ,1998: Carotid arterial stiffness as a predictor of cardiovascular and all-cause mortality in end stage renal disease.Hypertension ; 32 : 5574.
London GM, Marchais SJ, Guerin AP, Boutouyrie P, Metivier F, and De Vernejoul MC. ,2008: Association of bone activity, calcium load, aortic stiffness, and calcification in ESRD. J Am Soc Nephrol; ;19: 181835.
Kawagishi T, Nishizawa Y, Konishi T, Kawasaki K, Emoto M, Shoji T, Tabata T, Inoue T, Morii H.,1995:High-resolution B-mode ultrasonography in evaluation of atherosclerosis in uremia. Kidney Int ; 48 : 8826.
Saritas T, Tascilar E, Abaci A, Yozgat Y, Dogan M, Dundaroz R, Hasimi A, Yesilkaya E, Lenk MK and Kilic A., 2010: Importance of plasma N-terminal pro B-type natriuretic peptide, epicardial adipose tissue, and carotid intima-media thicknesses in asymptomatic obese children. Pediatr Cardiol. ; 31(6):79.
London GM, Guerin AP, Marchais SJ, Pannier B, Safar ME, Day M, Metivier F.,1996: Cardiac and arterial interactions in end-stage renal disease. Kidney Int ; 50:600 -608.
Davies MR, Lund RJ, Hruska KA., 2003: BMP-7 is an efficacious treatment of vascular calcification in a murine model of atherosclerosis and chronic renal failure. J Am Soc Nephrol ; 14: 1559–1567.
Mizobuchi M, Ogata H, Koiwa F, Kinugasa E, Akizawa T., 2009: Vitamin D and vascular calcification in chronic kidney disease. Bone ; 45: 26–29.
Drechsler C, Pilz S, Obermayer-Pietsch B, Verduijn M, Tomaschitz A, Krane V, Espe K,Dekker F, Brandenburg V, März W, Ritz E, Wanner C, 2010: Vitamin D deficiency is associated with sudden cardiac death, combined cardiovascular events, and mortality in haemodialysis patients. Eur Heart J; 31:2253–2261.
Prosdocimo DA, Wyler SC, Romani AM, O’Neill WC, Dubyak GR., 2010: Regulation of vascularsmooth muscle cell calcification by extracellular pyrophosphate homeostasis: synergistic modulation by cyclic AMP and hyperphosphatemia. Am J Physiol Cell Physiol ; 298:702–713.
Caglar K, Yilmaz MI, Saglam M, Cakir E, Kilic S, Sonmez A, Eyileten T, Yenicesu M, Oguz Y, Tasar M, Vural A, Ikizler TA, Stenvinkel P, Lindholm B., 2008:Serum fetuin-A concentration and endothelial dysfunction in chronic kidney disease. Nephron Clin Pract. 108:233–240.
Cottone S, Palermo A, Arsena R, Riccobene R, Guarneri M, Mulè G., 2010: Relationship of fetuin-A with glomerular filtration rate and endothelial dysfunction in moderate-severe chronic kidney disease. JNEPHROL ; 23(01):62–69
Moe SM and Chen NX., 2005: Inflammation and vascular calcification. Blood Purif.; 23:64–71.
Wang AY, Woo J, Lam CW, Wang M, Chan IH, Gao P, Liu SF, Li PK, Sanderson JE., 2005: Associations of serum fetuin-A with malnutrition, inflammation, atherosclerosis and valvular calcification syndrome and outcome in peritoneal dialysis patients. Nephrol Dial Transplant. ; 20:1676–1685.
Kazama JJ, Shigematsu T, Yano K, Tsuda E, Miura M, Iwasaki Y. ,2002: Increased circulating levels of osteoclastogenesis inhibitory factor (osteoprotegerin) in patients with chronic renal failure. Am J Kidney Dis.; 39:525–532.
Grzegorzewska AE and Mlot M., 2004: Serum osteoprotegerin level is lower in peritoneal dialysis patients than hemodialysis ones.Rocz Akad Med Bialymst. ; 49:193–196.