Danuta Fedak1, Marek Kuźniewski2, Paulina Dumnicka3, Maria Kapusta1, Grzegorz Chmiel2, Bogdan Solnica1, *Władysław Sułowicz2
Association between serum fetuin-A concentrations and vascular calcifications among patients on maintenance hemodialysis**
Związek pomiędzy stężeniem fetuiny-A w surowicy i zwapnieniami naczyniowymi u chorych leczonych powtarzanymi hemodializami
1Department of Diagnostics, Chair of Clinical Biochemistry, Jagiellonian University Medical College, Kraków
Head of Department: Professor Bogdan Solnica, MD, PhD
2Chair and Department of Nephrology, Jagiellonian University Medical College, Kraków
Head of Department: Professor Władysław Sułowicz, MD, PhD
3Department of Medical Diagnostics, Jagiellonian University Medical College, Kraków
Head of Department: Associate Professor Ryszard Drożdż, MD, PhD
Streszczenie
Wstęp. Zwapnienia naczyniowe u pacjentów ze schyłkową niewydolnością nerek leczonych powtarzanymi hemodializami są główną przyczyną zdarzeń sercowo-naczyniowych i zgonów. W badaniach epidemiologicznych wykazano, że duże zwapnienia naczyniowe i związane z nimi ryzyko chorobowości i śmiertelności występują szczególnie u chorych z niskimi stężeniami fetuiny-A w surowicy.
Cel pracy. Celem badania była ocena nasilenia zwapnień w układzie sercowo-naczyniowym u chorych leczonych powtarzanymi hemodializami w zależności od stężenia w surowicy fetuiny-A, gęstości mineralnej kości (BMD) i wskaźników zapalenia.
Materiał i metody. Badania przeprowadzono w grupie 71 pacjentów (31 kobiet, 40 mężczyzn) w wieku 60 ± 12 lat leczonych powtarzanymi dializami z powodu schyłkowej niewydolności nerek przez okres 75 ± 57,2 miesiąca. Nasilenie zwapnień w naczyniach oceniano w oparciu o wskaźnik uwapnienia naczyń wieńcowych (CaSc) i grubość kompleksu błony wewnętrznej i środkowej tętnicy szyjnej wspólnej (CCA-IMT). Gęstość mineralną kości mierzono przy użyciu aparatu Lunar DPX. Stężenie w surowicy rutynowo badanych wskaźników oceniano w aparacie Modular P analyzer (Roche Diagnostics), iPTH w oparciu o metodę Nicholsa, hsCRP i IL-6 przy użyciu techniki nefelometrycznej, podczas gdy fetuinę-A oznaczano w oparciu o zestawy ELISA.
Wyniki. W badaniu densytometrycznym wykazano obniżoną gęstość w zakresie kości udowej (Tscore = -2,0 ± 1,00) i odcinka lędźwiowego kręgosłupa (Tscore = -1,03 ± 1,51). Wskaźnik uwapnienia wskazywał na nasilone zwapnienia; CaSc – 511 (158-2394) jednostek Agatstona, a CCA-IMT – 0,90 ± 0,42. Stężenia fetuiny-A były istotnie ujemnie związane z wiekiem pacjentów (r = -0,26; p = 0,04), log (iPTH) (r = -0,31; p = 0,02), log (CRP) (r= -0.31, p = 0.02), log (IL-6) (r = -0.41, p = 0.001), log (CaSc) (r = -0,29; p = 0,03) i log (CCA-IMT) (r = -0,28; p = 0,04). Stężenia fetuiny-A dodatnio korelowały z albuminą (r = 0,37; p = 0,003) i BMD w okolicy szyjki kości udowej (r = 0,26; p = 0,04).
Wnioski. Pacjenci leczeni powtarzanymi hemodializami mają zaawansowane zwapnienia w układzie naczyniowym. Niskie stężenia fetuiny-A w surowicy są ujemnie związane ze wskaźnikami uwapnienia, zapaleniem i nadczynnością przytarczyc.
Summary
Introduction. Vascular calcifications in patients with end stage renal disease on maintenance hemodialysis is the leading cause of cardiovascular events and death. Epidemiological studies have shown that severe vascular calcifications and associated increased risk of morbidity and mortality occur particularly in patients with reduced serum fetuin-A levels.
Aim. The aim of the study was to assess the severity of calcifications in the cardiovascular system of patients treated with repeated hemodialysis depending on the concentrations of serum fetuin-A, bone mineral density (BMD) and markers of inflammation.
Material and methods. The study was performed in 71 patients (31 women, 40 men) aged 60 ± 12 years on chronic dialysis because of end-stage renal failure for a period of approximately 75 ± 57.2 months. The level of vascular calcifications was examined based on coronary artery calcification score (CaSc) and common carotid artery intima-media thickness (CCA-IMT). Bone mineral density was measured using Lunar DPX. The serum concentrations of routine laboratory test were performed based on Modular P analyzer (Roche Diagnostics), iPTH using Nichols method, hsCRP and IL-6 using nephelometric techniques while fetuin A, was measured using commercially available ELISA kits.
Results. Densitometry showed a decrease in bone mineral density both within the ranks of the femur (Tscore = -2.10 ± 1.00) and lumbar spine (Tscore = -1.03 ± 1.51). Calcium scoring performed in patients showed severe calcification; CaSc – 511 (158-2394) Agatston units and the CCA-IMT was 0.90 ± 0.42. Fetuin-A concentrations were significantly negatively associated with patients age (r = -0.26, p = 0.04), log (iPTH) (r = -0.31, p = 0.02), log (CRP) (r= -0.31, p = 0.02), log (IL-6) (r = -0.41, p = 0.001), log (CaSc) (r = -0.29, p = 0.03) and log (CCA-IMT) (r = -0.28, p = 0.04). Concentrations of fetuin-A were positively correlated with albumin (r = 0.37, p = 0.003) and BMD in the region of femoral neck (r = 0.26, p = 0.04).
Conclusions. Patients on maintenance hemodialysis suffer from severe calcifications of vascular system. Low serum fetuin-A levels are negatively associated with calcification parameters, inflammation and hyperparathyroidism.
Introduction
Cardiovascular diseases are the leading cause of death in the population of patients with end stage renal disease on maintenance hemodialysis. The increased cardiovascular mortality in dialysis patients may be influenced by many factors, such as advanced age, atherosclerosis, chronic inflammation, malnutrition, hypertension, anemia, diabetes, left ventricular hypertrophy (LVH) and vascular calcification in the course of secondary hyperparathyroidism (1-3). Vascular calcifications may be observed even in the early decades of life in patients with end-stage renal disease (ESRD) and severity of calcification increases with the progression of renal failure (2-6).
Epidemiological studies have shown that severe vascular calcifications and associated increased risk of mortality occur particularly in patients with reduced serum fetuin-A levels (7-9). The fetuin-A acts as an inhibitor of extraosseous calcification (10-14), it inhibits the de novo formation of hydroxyapatite crystals, at least in part, causing the sequestration of calcium and phosphate, and preventing their precipitation in serum containing these minerals (12, 15). The fetuin-A accumulates in the vascular calcification (16) and its serum levels reduction in patients with ESRD is inversely correlated with the occurrence of calcification of the coronary arteries (17-20).
It was also found that in patients with ESRD calcified plaques were higher in those with low bone density (21). It was also demonstrated that reduced bone mineralization in patients with chronic kidney disease (CKD), or in post-menopausal women are accompanied with increased calcifications of tissues, especially vascular system (22-24).
Aim
The aim of the study was to assess the severity of calcifications in the cardiovascular system in patients treated with repeated hemodialysis depending on the concentrations of serum fetuin-A, bone mineral density and markers of inflammation.
Material and methods
The study included 71 patients (31 women, 40 men) aged 60 ± 12 years on chronic dialysis because of end-stage renal failure for a period of approximately 75 ± 57.2 months. The cause of ESRD was chronic glomerulonephritis – 16 patients, chronic pyelonephritis – 16, kidney cirrhosis – 18, polycystic kidney disease – 10, diabetic nephropathy – 3 and not known cause of ESRD – 8. From the study group 55 patients had been treated for hypertension, and 8 had diabetes mellitus type 2. None of the patients had an active infections at the time of the study.
In 35 patients ischemic heart disease was diagnosed.
The basic demographic data and the results obtained are shown in table 1. Blood samples for routine laboratory tests were taken before hemodialysis start in the middle of the week sessions. The basic biochemical studies have been performed on the analyzer Modular P (Roche Diagnostic), C-reactive protein and IL-6 using immunonephelometric techniques Behring Nephelometer II, Dade Behring, Marburg, Germany while iPTH based on chemiluminescence Nichols method. The serum concentration of fetuin-A were measured using commercially available ELISA kits. Blood samples were centrifuged and the resulting serum/plasma aliquoted and stored at -70°C until immunoassays measurement. Routine laboratory tests were performed in the Diagnostic Laboratory at the University Hospital in Kraków, and immunochemical tests in Diagnostics Department, Jagiellonian University Medical College in Kraków.
Tab. 1. Demographic and clinical data of hemodialysis patients
| Studied parameters | Whole group (N = 71) | Women (N = 31) | Men (N = 40) | p-value |
| Age (years) | 60 ± 12 | 61 ± 14 | 59 ± 12 | 0.5 |
| Dialysis vintage (months) | 60 (36-100) | 52 (30-108) | 60 (45-97) | 0.8 |
| BMI (kg/m2) | 23.6 (21.0-26.7) | 22.0 (20.0-25.5) | 24.8 (22.6-28.0) | 0.01* |
| Hypertension | 55 (77%) | 23 (74%) | 32 (80%) | 0.6 |
| Diabetes mellitus type 2 | 8 (11%) | 2 (6%) | 6 (15%) | 0.5 |
| Ischemic heart disease | 35 (49%) | 19 (61%) | 16 (40%) | 0.08 |
| Smoking | 15 (21%) | 5 (16%) | 10 (25%) | 0.4 |
| BMD femoral neck (g/cm2) | 0.77 ± 0.17 | 0.73 ± 0.16 | 0.81 ± 0.17 | 0.07 |
| BMD lumbar spine (g/cm2) | 1.08 ± 0.24 | 0.96 ± 0.20 | 1.17 ± 0.23 | 0.0004* |
| CaSc (Agatstone units) | 488 (109-1853) | 462 (41-1428) | 511 (158-2394) | 0.5 |
| CCA-IMT (mm) | 0.90 (0.80-1.05) | 0.90 (0.75-1.00) | 0.90 (0.80-1.05) | 0.3 |
Values that were normally distributed, expressed as mean ± SD, data that were not normally distributed, expressed as median and (minimum-maximum), categorical variables are presented as %. *Significant associations
BM – body mass index; BMD – bone mineral density; CaSc – calcium scoring; CCA-IMT – common carotid artery intima-media thickness
The study was approved by the Jagiellonian University Bioethics Committee and all the patients gave written informed consent for participation.
Imaging techniques
The calcification score was measured by 64-slice spiral computer tomography scans, MSCT (Siemens Medical Solutions Inc., Germany) using the standard calcium scoring protocol. To quantify the calcification of the coronary arteries indicator of coronary artery calcification was used, expressed in units of numerical values forming the sum of the Agatston score for final calcification of the coronary arteries (CaSc). Common carotid artery intima-media thickness (CCA-IMT) measurements were performed using a ALOKA 5500 SV equipped with a head for vascular studies. The CCA-IMT of the medial trunk-internal carotid artery was measured at three locations: at the height of half the length of the common carotid artery; at a distance of 1 cm from the bifurcation of the common carotid artery and at the height of the pad common carotid artery. In each of the three points a 2-3 medial thickness measurements during the diastolic phase of the cardiac cycle were performed, and the final results were calculated as an average arithmetic values at a point of measurement. Both, CaSc and CCA-IMT were performed at the Center for Diagnosis and Rehabilitation of Heart and Lung Diseases Specialist Pope John Paul II Hospital in Kraków. Bone mineral density (BMD) was performed in the Metabolic Diseases Clinic of the University Hospital in Kraków using Dual Energy X-ray Absorptiometry, Lunar DPX (Lunar, USA). BMD was measured in the lumbar spine (L1-L4) and femoral region (Ward’s triangle).
Statistical analysis
The obtained data were reported as number (percent) and analyzed with Chi-squared test. Mean ± standard deviation (SD) or median (Lower-upper quartile) according distribution were given. Simple and multiple regression models were computed after log10-transformation of right-skewed variables.
The results were considered significant at p ≤ 0.05.
Results
The results of routine laboratory parameters, concentration of fetuin-A and imaging studies in the analyzed group of patients are summarized in table 1. Densitometry showed a decrease in bone mineral density both within the ranks of the femur (Tscore = -2.10 ± 1.00) and lumbar spine (Tscore = -1.03 ± 1.51). Calcium scoring performed in patients showed severe calcification of the vascular system, CaSc – 511 (158-2394) Agatston units and the CCA-IMT was 0.90 ± 0.42.
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