Supplementary Material for: Serum Calcification Propensity and Fetuin-A: Biomarkers of Cardiovascular Disease in Kidney Transplant Recipients
Andrew G. BostomAndreas PaschTracy E. MadsenMary B. RobertsNora FranceschiniDominik SteublP.S. GarimellaJoachim H. IxKatherine R. TuttleAnastasia IvanovaTheresa I. ShiremanReginald GohhBasma MerhiPetr Jarolı́mJohn W. KusekMarc A. PfefferSimin LiuCharles B. Eaton
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Background: “T50,” shortened transformation time from primary to secondary calciprotein particles may reflect deranged mineral metabolism predisposing to vascular calcification and cardiovascular disease (CVD). The glycoprotein fetuin-A is a major T50 determinant. Methods: The Folic Acid For Vascular Outcome Prevention In Transplantation (FAVORIT) cohort is a completed, large, multiethnic controlled clinical trial cohort of chronic, stable kidney transplant recipients (KTRs). We conducted a longitudinal case-cohort analysis using a randomly selected subcohort of patients, and all individual cases who developed CVD. Serum T50 and fetuin-A were determined in this total of n = 685 FAVORIT trial participants at randomization. Results: During a median surveillance of 2.18-years, 311 incident or recurrent CVD events occurred. Shorter T50 (minutes) or reduced fetuin-A concentrations (g/L) were associated with CVD after adjustment for treatment assignment, systolic blood pressure, age, sex, race, preexisting CVD and diabetes, smoking, body mass index, total cholesterol/HDL cholesterol, kidney allograft vintage and type, calcineurin inhibitor, or lipid-lowering drug use, estimated glomerular filtration rate, and urinary albumin/creatinine: tertile 1 (lowest) to tertile 3 (highest) comparisons, T50, (hazard ratio [HR] 1.86; 95% CI 1.20–2.89); fetuin-A, (HR 2.25; 95% CI 1.38–3.69). Elevated high sensitivity c-reactive protein (hsCRP) was an effect modifier of both these associations. Conclusions: Shortened T50, as well as reduced fetuin-A levels, ostensible promoters of vascular calcification, remained associated with greater risk for CVD outcomes, after adjustment for major CVD risk factors, measures of kidney function and damage, and KTR clinical characteristics and demographics, in a large, multiethnic cohort of long-term KTRs. Increased hsCRP was an effect modifier of these CVD risk associations.Keywords:
Fetuin
A variety of cell types in culture respond to fetuin, a glycoprotein from fetal bovine serum, which is often an important supplement to many serum-free media. Bovine fetuin preparation has been shown to inhibit trypsin activity and promote cellular attachment, growth, and differentiation in many different culture systems. In addition, fetuin associates with various growth factors or growth-promoting substances. However, whether the growth-promoting activity of fetuin preparation is due to fetuin per se or to its minor contaminant(s) has been a long-standing puzzle. The present review surveys the literature concerning this enigmatic property of fetuin and summarizes three possibilities: 1) fetuin itself is active, although the majority of studies do not support this; 2) various contaminants of fetuin preparations, including potentially unidentified ones, are responsible for the activity, a possibility supported by numerous reports; and 3) one of the fetuin subspecies, one of its contaminants, or a combination of both of these is responsible for growth of a specific cell type. In addition, the basic physicochemical properties and other biological functions of fetuin have also been presented.
Fetuin
Fetal bovine serum
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Human fetuin-A has emerged as a provocative molecule which actions in pregnancy have become the subject of research especially since the last decade. Also known as alpha-2 HeremansSchmid glycoprotein, fetuin-A is a circulating glycoprotein produced in increased amounts during fetal life by various tissues. Similar fetuin-A concentrations in maternal serum and umbilical cord suggest passive placental transfer of fetuin-A during pregnancy [1]. The concentration of fetuin-A in plasma decreases soon after delivery [2]. In the adult life, it is actively secreted into the blood stream mainly by the liver [3]. Research investigating the effects of fetuin-A in pregnancy has emerged after the following concepts:
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透析患者の血管石灰化は動脈硬化を重症化させる深刻な問題である．Fetuin-A（alpha 2-Heremans-Schmid glycoprotein）は血管石灰化を抑制する作用を有し，透析患者においては栄養障害・炎症とも関与していることから，動脈硬化関連因子でもある．われわれは，血液透析患者に対し頸動脈エコーを経時的に施行し，動脈硬化の程度（石灰化および内中膜肥厚）とFetuin-A濃度との関連性について検討した．対象78例の平均年齢は59.5歳，平均透析歴は90.9か月である．頸動脈エコーは2005年と2008年に施行した．Bモードにて総頸動脈を描出した後，プラークを含めた内中膜の厚さ（intima media thickness）を測定し，両側の総和をIMTとした．また，描出範囲内での内中膜あるいはプラークの石灰化の有無を観察した．血清中のFetuin-A濃度は2008年にELISA法にて測定した．頸動脈に石灰化を保有する群では保有しない群にくらべIMTが有意に高値であったが，Fetuin-A濃度に差はなかった．次に，Fetuin-A濃度の平均値0.235 g/Lを基準として対象を2群に分け，比較したところ，Fetuin-A＜0.24 g/Lの低値群のIMTの増加ΔIMTが有意に高値（p＝0.022）であった．3年間に頸動脈石灰化の進展を認めた症例は18例であった．15例がFetuin-A＜0.24 g/Lの低値群であり，Fetuin-A≥0.24 g/L高値群の3例にくらべると，その割合は有意に高かった（p＝0.001）．また，Fetuin-A濃度とIMTに相関性はなかったが，ΔIMTとは負相関（r＝－0.276，p＝0.014）を認めた．以上より，血液透析患者におけるFetuin-A濃度の低値が頸動脈石灰化および内中膜肥厚の進展に関与している可能性が考えられた．
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Intima-media thickness
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Fetuin
Sialoglycoproteins
Sepharose
Sialidase
Sialoglycoproteins
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Fetuin is a plasma glycoprotein widely distributed in mammals. It has been used as a model protein for structural analyses and investigations into the biological properties of glycoproteins. A convenient one-step procedure for biospecific isolation of fetuin from fetal bovine serum was developed on the basis of wheatgerm agglutinin (WGA) affinity separation. Two different porous supports, a silica-based material and a polymer-based material, were used for the immobilization of WGA. The prepared WGA adsorbents were characterized and process parameters of the affinity separation of fetuin were investigated and optimized. WGA was immobilized on silica and polymer supports with coupling yields of 99.6 and 99.4% respectively and amounts of coupled ligand of 7.9 and 9.2 mg of WGA/ml respectively. It has been shown that the specific capacities for fetuin were 5.1 mg/ml on WGA-silica, 1.8 mg/ml on WGA-polymer and 4.1 mg/ml on WGA-agarose. All three adsorbents proved to be suitable for the biospecific separation of fetuin. The polymer-based WGA adsorbent was successfully applied in the purification of fetuin from fetal bovine serum in a one-step separation process. The identity and purity of the isolated product was verified by SDS/PAGE. Under optimized conditions up to 21.6 mg of fetuin could be isolated from 1 ml of serum. The procedure described was designed to be easily scaled-up for the production of fetuin.
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Agarose
Fetal bovine serum
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Aim: Fetuin A is a multifunctional protein which is a marker of pathological calcification in several diseases. This study aimed to evaluate serum fetuin A level in term pregnancies with grade 3 placental calcification.
Material and Method: Fifty-seven pregnant women who applied obstetrics outpatient clinic for routine pregnancy follow-up at term were included in this study. The study was designed prospectively. Patients with grade 3 placental calcification (n=29) were compared to patients with non-calcified placenta (n=28) in terms of serum fetuin A levels.
Results: Maternal serum calcium levels of pregnant women with grade 3 calcified was significantly increased compared to pregnant women with non-calcified placenta. There was no significant difference between the fetuin A levels of study and control groups. The fetuin A level was not found to be correlated with maternal serum calcium level.
Conclusion: Fetuin A has been targeted as a marker for pathological calcification. The findings of the current study may support the thought that term placental calcification may be physiological rather than a pathological process.
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Fetuin, an abundant protein in fetal bovine plasma, is the bovine homolog of human alpha 2HS glycoprotein (alpha 2HS). In spite of numerous studies, the biological functions of both proteins remain elusive. We now report the remarkable 45Ca-binding activity of fetuin in fetal bovine serum that has been blotted on a membrane after electrophoresis. The Ca-binding ability of the purified protein was analyzed by equilibrium dialysis, which revealed that bovine fetuin had multiple Ca-binding sites, one of which had a Kd of 0.95 x 10(-4) M. It was also shown that the Ca-binding activity of fetuin was greater than that of albumin in serum of the bovine fetus at the late gestational stage. Since fetal bovine serum contains not only a high concentration of fetuin but also a high concentration of Ca, it is possible that fetuin functions to maintain high levels of Ca in fetal serum via normalization of the concentration of Ca2+ ions.
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Bovine serum albumin
Fetal bovine serum
Serum Albumin
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The importance of cardiovascular disease in adults with chronic kidney disease is now well recognized. For children who develop chronic kidney disease, cardiovascular disease is also a leading cause of eventual morbidity and mortality. Although the clinical manifestations of cardiovascular disease may not be apparent until later, early subclinical findings can be observed even during childhood. This review updates the reader on the epidemiology of cardiovascular disease in pediatric chronic kidney disease, discusses risk factors and potential mechanisms of accelerated cardiovascular disease, reviews evidence of early manifestations of cardiovascular disease in pediatric chronic kidney disease, and briefly discusses prevention and treatment strategies.
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The effects of bovine fetuin O-glycans on its trypsin inhibitory activity were examined. De-sialylated (asialo-) and de-O-glycosylated fetuin were prepared from native fetuin using Arthrobacter neuraminidase and the mixture of it and Bacillus endo-α-N-acetylgalactosaminidase, respectively. De-sialylation and de-O-glycosylation from fetuin were confirmed with SDS-PAGE followed by western blotting using anti-human Thomsen-Friedenreich antigen (T antigen) antibody which recognizes O-linked galactosyl β1,3 N-acetylgalactosamine (Galβ1→3GalNAc). Native fetuin completely inhibited the trypsin activity at about a 1:1 molar ratio. In contrast, the trypsin inhibitory activity of asialo- and de-O-glycosylated fetuin decreased about a half and one-third of that of native fetuin, respectively.
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Inflammatory diseases are associated with reduced serum concentrations of α2-HS glycoprotein (the human homologue of bovine fetuin), but the role of fetuin in inflammation is poorly understood. We hypothesized that fetuin may influence the resolution of inflammation by modulating the phagocytosis of apoptotic cells by macrophages. Using an in vitro flow cytometry-based phagocytosis assay, we investigated the role of fetuin in apoptotic cell clearance. Bovine fetuin and human α2-HS glycoprotein significantly augmented the phagocytosis of apoptotic cells by human peripheral blood monocyte-derived macrophages, whereas the control proteins BSA, sialylated BSA and asialofetuin were ineffective. The enhancement of phagocytosis was concentration-dependent, and required the presence of intact fetuin at the time of interaction between macrophages and apoptotic cells. Fetuin also substantially increased the uptake of labelled dextran 70000 by macrophages, which occurs by macropinocytosis, suggesting that this may be one of the mechanisms utilized for apoptotic cell uptake.
Fetuin
Pinocytosis
efferocytosis
Monocyte
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