- Email: [email protected]
Relationship Between Fetuin-A Concentration, Elevated Levels of Inflammatory Markers, and Arterial Wall Stiffness in End-Stage Kidney Disease
Relationship Between Fetuin-A Concentration, Elevated Levels of Inflammatory Markers, and Arterial Wall Stiffness in End-Stage Kidney Disease Jakub Kuz´niar, MD, PhD, Tomasz Porazko, _ MD, PhD, and Marian Klinger, MD, PhD The risk of cardiovascular mortality is significantly heightened in chronic dialysis patients. Aortic wall stiffness, as reflected by aortic pulse-wave velocity (PWV), is a strong predictor of cardiovascular events. Loss of the aortic wall’s elasticity is accelerated in dialysis patients because of calcifying medial arteriosclerosis, an active cellular process, controlled by calcification inducers and inhibitors. A pivotal role in the inhibition of calcium 3 phosphorus (Ca 3 P) precipitation is played by fetuin-A, a circulating plasma glycoprotein. In hemodialysis patients, lower fetuin-A concentrations were associated with increases in both cardiovascular and overall mortality. In our own study, a significant negative correlation was established between fetuin-A level and aortic PWV in chronic hemodialysis patients. The arterial-stiffening process was unaffected by the Ca 3 P product, but occurred independent of elevated interleukin-6 levels. Ó 2008 by the National Kidney Foundation, Inc.
I
T IS WIDELY DOCUMENTED THAT chronic dialysis patients suffer from excessive morbidity and mortality. In the 25-to-34-year age category, the risk of death is tremendously (even a thousand-fold) higher for end-stage renal disease (ESRD) patients than in the age-matched general population. Although this difference levels out with time, it is still 100 times greater for patients aged 45 years than in general-population counterparts.1 It is seldom mentioned that the 5year life expectancy for 50-year-old chronic dialysis patients is lower than for age-matched patients newly diagnosed with prostate or colon cancer. Cardiovascular causes account for nearly half of the deaths in ESRD patients. This exorbitant rate of cardiovascular mortality is well above expected if taking into account only ‘‘traditional’’ risk factors (i.e., age, sex, hyperlipidemia, smoking, hypertension, and diabetes).2 It becomes
Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland. Address reprint requests to Tomasz Porazko, _ MD, PhD, Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Ul. Traugutta 57/59, 50-417 Wrocław, Poland.
E-mail: [email protected] 2008 by the National Kidney Foundation, Inc. 1051-2276/08/1801-0016$34.00/0 doi:10.1053/j.jrn.2007.10.017
Ó
Journal of Renal Nutrition, Vol 18, No 1 (January), 2008: pp 83–86
quite obvious that this excess incidence of cardiovascular events in ESRD patients must result from additional, uremia-related risk factors, such as the intensity of inflammatory process, oxidative stress, endothelial dysfunction connected with high serum levels of homocysteine and asymmetrical dimethylarginine, and an accumulation of glycosylation end-products.
Aortic Wall Stiffness as Negative Prognostic Factor for Cardiovascular Mortality Extensive data are available regarding the negative impact of aortic wall stiffness on cardiovascular mortality.3 Pulse pressure (PP) is a simple indicator of aortic wall stiffness. However, more accurate than PP in the measurement of arterial wall elasticity is the determination of aortic pulse-wave velocity (PWV).4 Lack of compliance to systolic volume is a consequence of aortic wall stiffness. As a result, the aorta behaves purely as a conduit vessel, and does not exert a cushioning function. Even in the general population, survival rates show a strong negative correlation with PWV values. The 15year survival rates in the general-population cohort were at 95% for the low PWV tertile, 90% for the medium PWV tertile, and 80% for the 83
84
´ NIAR ET AL KUZ
high PWV tertile (highly significant difference between low and high tertile, at P , .0001).5 With regard to hemodialysis patients, in terms of the magnitude of PP, the hazard ratio for death was 3.8 for patients with a postdialysis PP of 80 to 90 mm Hg, compared with 0.5 for patients with a PP of 40 mm Hg.6
Calcification as the Cause of Accelerated Aortic Wall Stiffening in Chronic Kidney Disease Patients Age is the principal cause for the loss of aortic elasticity. However, it is also manifest that a decline in glomerular filtration rate (GFR) negatively affects aortic wall elasticity. A significant increase in aortic PWV was observed in association with even moderate drops in GFR to ,75 mL/min.7 As consequence of the joint effects of aging and uremia-related factors, loss of the elastic properties of the aortic wall is markedly accelerated in ESRD patients. This augmentation of arterial wall stiffness in ESRD patients is reflected by the fact that, in the general population, aortic PWV increases 9.0 6 0.4 cm per year for individuals aged 20 to 80 years, whereas in dialysis patients, this increase reaches 11.0 6 0.9 cm per year. This difference is statistically significant, at P , .01. It was recently documented that the acceleration of aortic wall-stiffening in dialysis patients is connected with medial calcification,8 an active cellular process controlled by calcification inducers and inhibitors.9 Also, extensive epidemiologic data demonstrate a link between calcium-phosphate metabolism derangements and cardiovascular mortality in dialysis patients.10 The list of calcification inducers in ESRD patients encompasses hypercalcemia, hyperphosphatemia, an elevated calcium 3 phosphorus (Ca 3 P) product, an increased parathyroid hormone level, and excessive treatment with vitamin D. Block el al. performed an analysis of the relationship between values of calcium-phosphate product and mortality risk, based on data obtained from 40,000 patients.10 They found evidence for an increase in relative death risk to 1.5 with a Ca 3 P product of 70 to 75 mg2/dL2, and to 1.8 with a Ca 3 P product .80 mg2/dL2. A significant increase in mortality risk (P ,.05) was associated with even relatively small rises in Ca 3 P product to 50 to 55 mg2/dL2.
Fetuin-A: A Potent Circulating Inhibitor of Vascular-Wall Calcification Without neglecting the significance of high calcium-phosphate product levels in the calcification process, it should be underscored that, even in healthy people, extracellular fluids are supersaturated with respect to calcium and phosphate, but widespread calcification still does not occur. This fact elucidates the role of calcification inhibitors: both local, such as matrix Gla-protein (MGP), and circulating, particularly fetuin-A. Fetuin-A (alpha – 2 – Heremans Schmid glycoprotein) is produced during fetal development by multiple tissues, whereas in adults it is synthetized predominantly by the liver.11 It is a member of the cystatin superfamily of cysteine protease inhibitors. Ablation of the mouse fetuin-A gene in a strain of calcification-prone mice results in a progressive, fatal calcification of soft tissues, including the kidney, testes, skin, heart, and vasculature.12 Fetuin-A constitutes the largest a2band in serum electrophoresis. Its normal serum concentration amounts to 0.5 to 1 g/L, and it is down-regulated under conditions of inflammation.13 Ketteler et al. reported on an inverse relationship between serum fetuin-A and C-reactive protein (CRP).14 In hemodialysis patients, lower fetuin-A concentrations were associated with both higher cardiovascular and overall mortality. Besides playing a pivotal role in the inhibition of Ca 3 P precipitation, fetuin-A exhibits additional anti-inflammatory and phagocytosis-promoting activity.15,16 Reynolds et al. explained the multiple mechanisms involved in the inhibition of vascular smooth muscle cell calcification (VSMC) (i.e., calcification of the medial layer of the vascular wall) by fetuinA.9 First, fetuin-A is taken up by VSMC into intracellular vesicles, where it prevents nucleation of insoluble basic calcium-phosphate (the formation of new crystal nuclei in a supersaturated solution). The nucleation of basic calcium-phosphate is one the earliest events in VSMC calcification, induced by high extracellular concentrations of Ca and P. At this point, fetuin-A acts as a binder of basic calcium-phosphate and as an inhibitor of spontaneous precipitation of Ca and P in solution. If nucleation occurs, vesicles loaded with Ca and P are released from VSMC, which is a protective mechanism to remove an excess of intracellular Ca. Fetuin-A
FETUIN-A, INFLAMMATORY MARKERS, AND ARTERIAL WALL STIFFNESS
promotes the phagocytosis of such calcium-loaded vesicles. This is the second novel biological effect of fetuin-A, in addition to its role in stabilizing Ca and P in serum and preventing its precipitation. In vivo localization of fetuin-A in atherosclerotic and ESRD arteries revealed that it is deposited at sites of calcification.17 This observation suggests that inhibition may be most relevant at, or restricted to, sites of vessel-wall damage, where VSMC becomes phenotypically modulated in response to injury.
Our Investigation of the Relationship Between Serum Fetuin-A Concentration and Aortic PulseWave Velocity The subject of the current study, published to date in abstract form,18,19 was the investigation of the relationship between fetuin-A concentration and aortic wall stiffness as measured by PWV. The study encompassed 49 chronic kidney disease (CKD) patients (stage 5, before initiation of dialysis treatment), 77 hemodialysis (HD) patients, 29 peritoneal dialysis (PD) patients, and 30 age-matched healthy volunteers. The PWV values in all patient groups were significantly higher (CKD, 9.63 6 2.09 m/sec; HD, 9.75 6 1.8 m/sec; PD, 9.06 6 1.71 m/sec) than in healthy controls (7.76 6 1.67 m/sec). These observations indicate that the process of aortic wallstiffening had already progressed prior to dialysis, and despite the average 3.5-year duration of HD treatment and .2-year-long PD treatment in our patients, no differences occurred in PWV values compared with patients before the initiation of dialysis. Serum fetuin-A concentrations were significantly lower in all patient groups (HD, 0.58 g/L [SD 6 0.19 g/L]; PD, 0.6 g/L [SD 6 0.22 g/L]; CKD, 0.63 g/L [SD 6 0.18 g/L]) than in healthy controls (0.86 g/L [SD 6 0.15 g/L]). Multiple linear regression analysis showed (in accordance with data published earlier) that age (P ,.001), systolic blood pressure (SBP) (P ,.002), and mean arterial blood pressure (P , .004) were independent factors significantly increasing PWV values in healthy volunteers. No relationships were found with respect to sex, body mass index (BMI), smoking, diastolic blood pressure (DBP), PP, cholesterol, high-density lipoprotein (HDL), triglicerides (TG), glucose, CRP, interleukin (IL)-6, IL-10, IL-18, and fetuin-A.
85
The same statistical approach, applied to HD patients, revealed a relationship with age similar to that in healthy controls (P ,.003) and an array of new associations between PWV and DBP (P , .003), PP (P ,.003) , BMI (P ,.009), interleukin (IL)-6 (P , .013), HDL (P , .036), and fetuin-A (P ,.049). However, no relationships were established with sex, smoking, diabetes, SBP, hemoglobin, serum albumin, fibrinogen, parathormone, Ca, P, total cholesterol, TG, glucose, CRP, and IL-10 levels. The low number of HD patients enrolled in this study limited our analysis of the data, but it is noteworthy that fetuin-A showed a significant negative correlation with aortic PWV, which did not appear in the case of the Ca 3 P product. This partly supports the assumption that the efficiency of calcification inhibitors is of an importance similar to that of control of the Ca 3 P product. Independent from IL-6, the effect of lower serum fetuin-A concentration on aortal PWV confirms that its role in the prevention of tissue calcification is not only associated with inflammatory process.
Conclusions Aortic wall stiffness, which is a strong predictor of cardiovascular mortality in CKD patients, has a multifactorial background. The aging process constitutes the main factor, as in the healthy population. In CKD patients, the aortic wall stiffness is amplified by inflammation, calcium and phosphorus burden, and the loss of calcification inhibitors, particularly fetuin-A.
References 1. US Renal Data System: USRDS 1998 annual data report. Bethesda, MD: National Institute of Diabetes and Kidney Disease, 1999, pp 63-70 2. Foley RN, Murray AM, Li S, et al: Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999. J Am Soc Nephrol 16:489-495, 2005 3. Asmar R, Rudnichi A, Blacher J, London GM, Safar ME: Pulse pressure and aortic pulse wave are markers of cardiovascular risk in hypertensive populations. Am J Hypertens 14:91-97, 2001 4. Blacher J, Safar ME, Guerin AP, Pannier B, Marchais SJ, London GM: Aortic pulse wave velocity index and mortality in end-stage renal disease. Kidney Int 63:1852-1860, 2003 5. Laurent S, Boutouyrie P, Asmar R, et al: Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 37:1236-1241, 2001
86
´ NIAR ET AL KUZ
6. Klassen PS, Lowrie EG, Reddan DN, et al: Association between pulse pressure and mortality in patients undergoing maintenance hemodialysis. JAMA 287:1548-1555, 2002 7. Mourad JJ, Pannier B, Blacher J, et al: Creatinine clearance, pulse wave velocity, carotid compliance and essential hypertension. Kidney Int 59:1834-1841, 2001 8. Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM: Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 38:938–942, 2001 9. Reynolds JL, Skepper JN, McNair R, et al: Multifunctional roles for serum protein fetuin-A in inhibition of human vascular smooth muscle cell calcification. J Am Soc Nephrol 16: 2920-2930, 2005 10. Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM: Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 15:2208-2218, 2004 11. Brown WM, Saunders NR, Mollgard K, Dziegielewska KM: Fetuin—an old friend revisited. Bioessays 14:749-755, 1992 12. Jahnen-Dechent W, Schinke T, Trindl A, et al: Cloning and targeted deletion of the mouse fetuin gene. J Biol Chem 272: 31496-31503, 1997 13. 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 64:1118-1129, 1979 14. Ketteler M, Bongartz P, Westenfeld R, et al: Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet 361:827-833, 2003 15. Heiss A, DuChesne A, Denecke B, et al: Structural basis of calcification inhibition by alpha 2-HS glycoprotein/fetuin-A. Formation of colloidal calciprotein particles. J Biol Chem 278: 13333-13341, 2003 16. Jersmann HP, Dransfield I, Hart SP: Fetuin/alpha2-HS glycoprotein enhances phagocytosis of apoptotic cells and macropinocytosis by human macrophages. Clin Sci 105:273-278, 2003 17. Moe SM, Reslerova M, Ketteler M, et al: Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD). Kidney Int 67:2295-2304, 2005 18. Pora_zko T, Kuz´niar J, Kusztal M, Klinger M: Fetuin deficiency is associated with decreased elasticity of arterial wall in end-stage renal disease (ESRD) patients. J Am Soc Nephrol 16: 187A, 2005 19. Pora_zko T, Kuz´niar J, Kusztal M, Weyde W, Klinger M: Relationship between levels of C-reactive protein, interleukin (IL)-18, IL-10, a negative phase acute reactant—fetuin A and arterial stiffness in end-stage renal disease. Nephrol Dial Transplant 21(Suppl 4):429, 2006
I
T IS WIDELY DOCUMENTED THAT chronic dialysis patients suffer from excessive morbidity and mortality. In the 25-to-34-year age category, the risk of death is tremendously (even a thousand-fold) higher for end-stage renal disease (ESRD) patients than in the age-matched general population. Although this difference levels out with time, it is still 100 times greater for patients aged 45 years than in general-population counterparts.1 It is seldom mentioned that the 5year life expectancy for 50-year-old chronic dialysis patients is lower than for age-matched patients newly diagnosed with prostate or colon cancer. Cardiovascular causes account for nearly half of the deaths in ESRD patients. This exorbitant rate of cardiovascular mortality is well above expected if taking into account only ‘‘traditional’’ risk factors (i.e., age, sex, hyperlipidemia, smoking, hypertension, and diabetes).2 It becomes
Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland. Address reprint requests to Tomasz Porazko, _ MD, PhD, Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Ul. Traugutta 57/59, 50-417 Wrocław, Poland.
E-mail: [email protected] 2008 by the National Kidney Foundation, Inc. 1051-2276/08/1801-0016$34.00/0 doi:10.1053/j.jrn.2007.10.017
Ó
Journal of Renal Nutrition, Vol 18, No 1 (January), 2008: pp 83–86
quite obvious that this excess incidence of cardiovascular events in ESRD patients must result from additional, uremia-related risk factors, such as the intensity of inflammatory process, oxidative stress, endothelial dysfunction connected with high serum levels of homocysteine and asymmetrical dimethylarginine, and an accumulation of glycosylation end-products.
Aortic Wall Stiffness as Negative Prognostic Factor for Cardiovascular Mortality Extensive data are available regarding the negative impact of aortic wall stiffness on cardiovascular mortality.3 Pulse pressure (PP) is a simple indicator of aortic wall stiffness. However, more accurate than PP in the measurement of arterial wall elasticity is the determination of aortic pulse-wave velocity (PWV).4 Lack of compliance to systolic volume is a consequence of aortic wall stiffness. As a result, the aorta behaves purely as a conduit vessel, and does not exert a cushioning function. Even in the general population, survival rates show a strong negative correlation with PWV values. The 15year survival rates in the general-population cohort were at 95% for the low PWV tertile, 90% for the medium PWV tertile, and 80% for the 83
84
´ NIAR ET AL KUZ
high PWV tertile (highly significant difference between low and high tertile, at P , .0001).5 With regard to hemodialysis patients, in terms of the magnitude of PP, the hazard ratio for death was 3.8 for patients with a postdialysis PP of 80 to 90 mm Hg, compared with 0.5 for patients with a PP of 40 mm Hg.6
Calcification as the Cause of Accelerated Aortic Wall Stiffening in Chronic Kidney Disease Patients Age is the principal cause for the loss of aortic elasticity. However, it is also manifest that a decline in glomerular filtration rate (GFR) negatively affects aortic wall elasticity. A significant increase in aortic PWV was observed in association with even moderate drops in GFR to ,75 mL/min.7 As consequence of the joint effects of aging and uremia-related factors, loss of the elastic properties of the aortic wall is markedly accelerated in ESRD patients. This augmentation of arterial wall stiffness in ESRD patients is reflected by the fact that, in the general population, aortic PWV increases 9.0 6 0.4 cm per year for individuals aged 20 to 80 years, whereas in dialysis patients, this increase reaches 11.0 6 0.9 cm per year. This difference is statistically significant, at P , .01. It was recently documented that the acceleration of aortic wall-stiffening in dialysis patients is connected with medial calcification,8 an active cellular process controlled by calcification inducers and inhibitors.9 Also, extensive epidemiologic data demonstrate a link between calcium-phosphate metabolism derangements and cardiovascular mortality in dialysis patients.10 The list of calcification inducers in ESRD patients encompasses hypercalcemia, hyperphosphatemia, an elevated calcium 3 phosphorus (Ca 3 P) product, an increased parathyroid hormone level, and excessive treatment with vitamin D. Block el al. performed an analysis of the relationship between values of calcium-phosphate product and mortality risk, based on data obtained from 40,000 patients.10 They found evidence for an increase in relative death risk to 1.5 with a Ca 3 P product of 70 to 75 mg2/dL2, and to 1.8 with a Ca 3 P product .80 mg2/dL2. A significant increase in mortality risk (P ,.05) was associated with even relatively small rises in Ca 3 P product to 50 to 55 mg2/dL2.
Fetuin-A: A Potent Circulating Inhibitor of Vascular-Wall Calcification Without neglecting the significance of high calcium-phosphate product levels in the calcification process, it should be underscored that, even in healthy people, extracellular fluids are supersaturated with respect to calcium and phosphate, but widespread calcification still does not occur. This fact elucidates the role of calcification inhibitors: both local, such as matrix Gla-protein (MGP), and circulating, particularly fetuin-A. Fetuin-A (alpha – 2 – Heremans Schmid glycoprotein) is produced during fetal development by multiple tissues, whereas in adults it is synthetized predominantly by the liver.11 It is a member of the cystatin superfamily of cysteine protease inhibitors. Ablation of the mouse fetuin-A gene in a strain of calcification-prone mice results in a progressive, fatal calcification of soft tissues, including the kidney, testes, skin, heart, and vasculature.12 Fetuin-A constitutes the largest a2band in serum electrophoresis. Its normal serum concentration amounts to 0.5 to 1 g/L, and it is down-regulated under conditions of inflammation.13 Ketteler et al. reported on an inverse relationship between serum fetuin-A and C-reactive protein (CRP).14 In hemodialysis patients, lower fetuin-A concentrations were associated with both higher cardiovascular and overall mortality. Besides playing a pivotal role in the inhibition of Ca 3 P precipitation, fetuin-A exhibits additional anti-inflammatory and phagocytosis-promoting activity.15,16 Reynolds et al. explained the multiple mechanisms involved in the inhibition of vascular smooth muscle cell calcification (VSMC) (i.e., calcification of the medial layer of the vascular wall) by fetuinA.9 First, fetuin-A is taken up by VSMC into intracellular vesicles, where it prevents nucleation of insoluble basic calcium-phosphate (the formation of new crystal nuclei in a supersaturated solution). The nucleation of basic calcium-phosphate is one the earliest events in VSMC calcification, induced by high extracellular concentrations of Ca and P. At this point, fetuin-A acts as a binder of basic calcium-phosphate and as an inhibitor of spontaneous precipitation of Ca and P in solution. If nucleation occurs, vesicles loaded with Ca and P are released from VSMC, which is a protective mechanism to remove an excess of intracellular Ca. Fetuin-A
FETUIN-A, INFLAMMATORY MARKERS, AND ARTERIAL WALL STIFFNESS
promotes the phagocytosis of such calcium-loaded vesicles. This is the second novel biological effect of fetuin-A, in addition to its role in stabilizing Ca and P in serum and preventing its precipitation. In vivo localization of fetuin-A in atherosclerotic and ESRD arteries revealed that it is deposited at sites of calcification.17 This observation suggests that inhibition may be most relevant at, or restricted to, sites of vessel-wall damage, where VSMC becomes phenotypically modulated in response to injury.
Our Investigation of the Relationship Between Serum Fetuin-A Concentration and Aortic PulseWave Velocity The subject of the current study, published to date in abstract form,18,19 was the investigation of the relationship between fetuin-A concentration and aortic wall stiffness as measured by PWV. The study encompassed 49 chronic kidney disease (CKD) patients (stage 5, before initiation of dialysis treatment), 77 hemodialysis (HD) patients, 29 peritoneal dialysis (PD) patients, and 30 age-matched healthy volunteers. The PWV values in all patient groups were significantly higher (CKD, 9.63 6 2.09 m/sec; HD, 9.75 6 1.8 m/sec; PD, 9.06 6 1.71 m/sec) than in healthy controls (7.76 6 1.67 m/sec). These observations indicate that the process of aortic wallstiffening had already progressed prior to dialysis, and despite the average 3.5-year duration of HD treatment and .2-year-long PD treatment in our patients, no differences occurred in PWV values compared with patients before the initiation of dialysis. Serum fetuin-A concentrations were significantly lower in all patient groups (HD, 0.58 g/L [SD 6 0.19 g/L]; PD, 0.6 g/L [SD 6 0.22 g/L]; CKD, 0.63 g/L [SD 6 0.18 g/L]) than in healthy controls (0.86 g/L [SD 6 0.15 g/L]). Multiple linear regression analysis showed (in accordance with data published earlier) that age (P ,.001), systolic blood pressure (SBP) (P ,.002), and mean arterial blood pressure (P , .004) were independent factors significantly increasing PWV values in healthy volunteers. No relationships were found with respect to sex, body mass index (BMI), smoking, diastolic blood pressure (DBP), PP, cholesterol, high-density lipoprotein (HDL), triglicerides (TG), glucose, CRP, interleukin (IL)-6, IL-10, IL-18, and fetuin-A.
85
The same statistical approach, applied to HD patients, revealed a relationship with age similar to that in healthy controls (P ,.003) and an array of new associations between PWV and DBP (P , .003), PP (P ,.003) , BMI (P ,.009), interleukin (IL)-6 (P , .013), HDL (P , .036), and fetuin-A (P ,.049). However, no relationships were established with sex, smoking, diabetes, SBP, hemoglobin, serum albumin, fibrinogen, parathormone, Ca, P, total cholesterol, TG, glucose, CRP, and IL-10 levels. The low number of HD patients enrolled in this study limited our analysis of the data, but it is noteworthy that fetuin-A showed a significant negative correlation with aortic PWV, which did not appear in the case of the Ca 3 P product. This partly supports the assumption that the efficiency of calcification inhibitors is of an importance similar to that of control of the Ca 3 P product. Independent from IL-6, the effect of lower serum fetuin-A concentration on aortal PWV confirms that its role in the prevention of tissue calcification is not only associated with inflammatory process.
Conclusions Aortic wall stiffness, which is a strong predictor of cardiovascular mortality in CKD patients, has a multifactorial background. The aging process constitutes the main factor, as in the healthy population. In CKD patients, the aortic wall stiffness is amplified by inflammation, calcium and phosphorus burden, and the loss of calcification inhibitors, particularly fetuin-A.
References 1. US Renal Data System: USRDS 1998 annual data report. Bethesda, MD: National Institute of Diabetes and Kidney Disease, 1999, pp 63-70 2. Foley RN, Murray AM, Li S, et al: Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999. J Am Soc Nephrol 16:489-495, 2005 3. Asmar R, Rudnichi A, Blacher J, London GM, Safar ME: Pulse pressure and aortic pulse wave are markers of cardiovascular risk in hypertensive populations. Am J Hypertens 14:91-97, 2001 4. Blacher J, Safar ME, Guerin AP, Pannier B, Marchais SJ, London GM: Aortic pulse wave velocity index and mortality in end-stage renal disease. Kidney Int 63:1852-1860, 2003 5. Laurent S, Boutouyrie P, Asmar R, et al: Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 37:1236-1241, 2001
86
´ NIAR ET AL KUZ
6. Klassen PS, Lowrie EG, Reddan DN, et al: Association between pulse pressure and mortality in patients undergoing maintenance hemodialysis. JAMA 287:1548-1555, 2002 7. Mourad JJ, Pannier B, Blacher J, et al: Creatinine clearance, pulse wave velocity, carotid compliance and essential hypertension. Kidney Int 59:1834-1841, 2001 8. Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM: Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 38:938–942, 2001 9. Reynolds JL, Skepper JN, McNair R, et al: Multifunctional roles for serum protein fetuin-A in inhibition of human vascular smooth muscle cell calcification. J Am Soc Nephrol 16: 2920-2930, 2005 10. Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM: Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 15:2208-2218, 2004 11. Brown WM, Saunders NR, Mollgard K, Dziegielewska KM: Fetuin—an old friend revisited. Bioessays 14:749-755, 1992 12. Jahnen-Dechent W, Schinke T, Trindl A, et al: Cloning and targeted deletion of the mouse fetuin gene. J Biol Chem 272: 31496-31503, 1997 13. 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 64:1118-1129, 1979 14. Ketteler M, Bongartz P, Westenfeld R, et al: Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet 361:827-833, 2003 15. Heiss A, DuChesne A, Denecke B, et al: Structural basis of calcification inhibition by alpha 2-HS glycoprotein/fetuin-A. Formation of colloidal calciprotein particles. J Biol Chem 278: 13333-13341, 2003 16. Jersmann HP, Dransfield I, Hart SP: Fetuin/alpha2-HS glycoprotein enhances phagocytosis of apoptotic cells and macropinocytosis by human macrophages. Clin Sci 105:273-278, 2003 17. Moe SM, Reslerova M, Ketteler M, et al: Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD). Kidney Int 67:2295-2304, 2005 18. Pora_zko T, Kuz´niar J, Kusztal M, Klinger M: Fetuin deficiency is associated with decreased elasticity of arterial wall in end-stage renal disease (ESRD) patients. J Am Soc Nephrol 16: 187A, 2005 19. Pora_zko T, Kuz´niar J, Kusztal M, Weyde W, Klinger M: Relationship between levels of C-reactive protein, interleukin (IL)-18, IL-10, a negative phase acute reactant—fetuin A and arterial stiffness in end-stage renal disease. Nephrol Dial Transplant 21(Suppl 4):429, 2006