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AJNT Arab Journal of Nephrology and Transplantation. 2013 Jan;6(1):11-20 Original Article Negative Correlation between Fetuin-A and Indices of Vascular Disease in Systemic Lupus Erythematosus Patients with and without Lupus Nephritis Ali F. I. Abdel-Wahab1*, Osama Fathy2 and Randa Al-Harizy3 1. Department of Pharmacology, Cairo University, Cairo, Egypt and Department of Health Sciences, Umm Al-Qura University, Makkah , KSA. 2. Department of Biochemistry, Umm Al-Qura University, Makkah, KSA. 3. Department of Internal Medicine, Cairo University, Cairo,Egypt. Abstract Keywords: Atherosclerosis; Fetuin-A; Lupus nephritis; SLE; Vascular Calcification. Introduction: Fetuin-A, a systemic calcification inhibitor, has been negatively related to vascular calcification (VC) and cardiovascular mortality. In this study we The authors declared no conflict of interest investigated the association between fetuin-A levels and atherosclerotic vascular complications in systemic lupus Introduction erythematosus (SLE) patients with and without lupus Systemic lupus erythematosus (SLE) is a multisystem nephritis (LN). autoimmune disease characterized by the production Methods: We recruited 20 SLE patients without LN, of autoantibodies, which can affect all organ systems, 20 SLE patients with LN and 20 healthy controls. We especially the kidneys. Premature and accelerated determined serum creatinine, lipid profile, high sensitivity atherosclerosis is increasingly recognized as being C-reactive protein (hsCRP), calcium, phosphate and prevalent in young female patients with SLE. fetuin-A levels, and calculated the calcification risk Cardiovascular disease (CVD) develops in 6-9% of index (CRI) and SLE disease activity index (SLEDAI) SLE patients and accounts for up to 36.4% of deaths for all subjects. Vascular disease burden was assessed by in SLE [1]. Moreover, lupus nephritis (LN) patients quantification of carotid artery intima-media-thickness (IMT) and the ankle-brachial index (ABI). develop chronic kidney disease (CKD) and experience cardiovascular disease risk that is much higher than that Results: Fetuin-A levels were significantly lower in in age- and sex-matched populations with normal kidney LN patients (0.47 ± 0.1 g/L) compared to SLE patients function [2]. Several epidemiological studies have without LN (0.54 ± 0.1 g/L) and both were significantly demonstrated accelerated vascular calcification in CKD lower than controls (0.78 ± 0.2 g/L). CRI was significantly [3, 4]. Pathological studies have shown that persons with higher in LN patients (89.1 ± 12.1 mg/L) compared to SLE patients without LN (67.2 ± 9.3 mg/L) and both end stage renal disease (ESRD) experience accelerated were significantly higher than controls (34.2 ± 6.2 mg/L). atherosclerosis, and also high rates of vascular medial Peripheral arterial disease (ABI < 0.9) was significantly calcification [5]. more common in LN patients (55%) compared to SLE Although traditional cardiovascular risk factors apply, patients without LN (30%) as well as controls (0%). lupus-associated activation of the immune system Fetuin-A levels showed significant negative correlations contributes to the accumulation of vascular damage with serum creatinine, hsCRP, CRI, IMT and ABI in SLE [6]. Defining the autoimmune mechanisms underlying patients with and without LN. these vascular complications is essential to optimize risk Conclusion: Fetuin-A levels were decreased in SLE reduction and develop targeted therapy for prevention of patients with and without LN and negatively correlated CVD in SLE patients. Vascular calcification (VC) in SLE with vascular complications. This suggests a potentially may be the main pathogenic factor underling CVD with important role for fetuin-A deficiency as marker of its associated morbidity. In fact, vascular disease can vascular disease in SLE patients with and without LN. practically be used as a diagnostic parameter to evaluate the severity of SLE [7]. Measurement of coronary * Corresponding Author; E. mail:

calcification may even help detect asymptomatic lupus Arab Journal of Nephrology and Transplantation 11 Abdel-Wahab, Fathy and Al-Harizy in patients. Such patients might benefit from aggressive ethics committee in Kasr El-Aini teaching hospital, Cairo interceptive measures, should their condition be detected University, and all participants signed a written informed early. Additionally, vascular calcification has far more consent. Patients and controls were subjected to full reaching and diverse effects in SLE; which reflects the medical history taking and thorough clinical examination. wider diversity of effects produced by vascular disease SLE patients fulfilled the diagnostic criteria of the when it is associated with SLE than it does in other American College of Rheumatology (revised in 1982 and circumstances [8]. updated in 1997) [15]. They were all females, their ages Vascular calcification (VC) was previously thought to ranged from 18-41 years, with a mean age of 27.3±6.1 be a passive process aggravated by hyperphosphatemia years. Exclusion criteria included dialysis dependency, and hypercalcemia that could be controlled adequately serum creatinine > 6 mg/dl, coagulation disturbances, with careful attention to mineral balance [9]. However, cancer, diabetes, current intake of oral contraceptives or accumulating evidence suggests that VC is a regulated hormone replacement therapy, the presence of any critical process affected by intra- and extra-cellular mechanisms illness within the last 6 months and specific treatment as well as serum-based proteins [10]. Because human with calcium supplements, phosphate binders, or vitamin serum is supersaturated with respect to calcium and D. The SLE disease activity was assessed at the time phosphorus, the existence of serum-based precipitation of enrollment in the study using the Systemic Lupus inhibitors has long been postulated. Human fetuin-A Erythematosus Disease Activity Index (SLEDAI) score. (alpha-2-Heremans Schmid glycoprotein), a protein The use of corticosteroid therapy was quantified in terms produced by the liver and secreted into serum in high of the average daily dose over the preceding five years concentrations, is a major serum-based inhibitor of of the study. SLE patients were divided into two groups VC and accounts for roughly 50% of the inhibition of according to the presence or absence of LN. Patients with calcium and phosphorous precipitation [11]. Several LN included also those who had documented proteinuria studies have linked low fetuin-A levels to VCs and flow- associated with hematuria or renal casts in at least two limiting aortic stenosis [12]. Also, fetuin-A has been separate urine samples in addition to patients with overt negatively related to VCs and cardiovascular mortality in CKD. The control group included twenty healthy females dialysis patients [13]. However, there are only scarce and whose age ranged from 19-43 years, with a mean age of contradictory data on fetuin-A levels in moderate CKD 29.2±5.4 years. All controls had no clinical evidence of and their effect on vessel health. Also, it is still unsolved cardiovascular disease, no evidence of SLE, nephropathy, whether in patients with kidney disease the basic biology or any immunological disturbances. underlying CVD is similar to that acknowledged for patients without kidney disease. Many other risk factors Urine and blood samples were collected from all subjects are present as a consequence of the renal dysfunction and for analysis. Blood was collected after an overnight fast thus involved in the accelerated atherosclerotic process (12 h) from the cubital vein. Serum samples were used [14]. The situation is even more complex in patients to determine the levels of blood urea nitrogen (BUN), with SLE, who generally suffer from advanced systemic serum creatinine, ANA, anti-dsDNA, triglycerides, total atherosclerosis. cholesterol and HDL cholesterol. LDL cholesterol levels were calculated by using the Friedewald formula [16]. To clarify the relation between fetuin-A and vascular High sensitivity C-reactive protein (hsCRP) was measured complications in SLE patients with and without lupus using the Roche Integra assay [17]. Complement C3 was nephritis, we studied the correlation between fetuin-A assayed by Assay Max Human C3 complement ELISA levels and parameters of kidney function, SLE disease kit (EC2101-1) [18]. Serum calcium was adjusted for activity, and vascular disease in SLE patients with and serum albumin according to the equation [19]: without LN. Adjusted calcium (mg/dl) = measured calcium (mg/ dl) + Methods [(4.0–serum albumin in g/dl) ×0.8] Forty SLE patients and twenty controls were randomly Inorganic phosphate level was measured by recruited from persons attending the internal medicine CHRONOLAB phosphomolybdate UV kit (101- 0458) department of Kasr El-Aini teaching hospital, Cairo, [20]. Fetuin-A was measured in duplicates by an ELISA Egypt. The study protocol was approved by the institutional (Epitope Diagnostics, Inc., San Diego, USA) according Arab Journal of Nephrology and Transplantation 12 Fetuin-A and Vascular Disease in SLE to the manufacturer’s protocol. The intra- and inter- assay disease duration. LN patients showed significantly higher variations were 5.3 and 7.1%, respectively [21]. SLEDAI score, BUN, serum creatinine and blood pressure readings compared with SLE patients without nephritis. The collected data were further used to calculate the All patients used steroids treatment during the course ‘Systemic Lupus Erythematosus Disease Activity Index’ of their disease. Other immunosuppressive treatments (SLEDAI) [23] and the ‘Calcification Risk Index’ (CRI) were used in 11 patients with LN (azathioprine in 5, and [22]. CRI was calculated by the formula: cyclophosphamide in 2 patients) and hydroxychloroquine CRI = Calcium level × inorganic phosphate level / in 4 patients. Fetuin-A The blood levels of calcium and inorganic phosphate For manifestations of atherosclerosis, we defined the were significantly higher in SLE patients compared intima-media thickness (IMT) of carotid arteries and with healthy control subjects. LN patients showed calculated the ankle-brachial index (ABI). The IMT, were significantly more elevations of phosphate level detected by carotid ultrasonography using high-resolution compared with SLE patients without nephritis. Fetuin-A B-mode ultrasound (Voluson 730 Kretz, Tiefenbach, levels were significantly lower in SLE patients with and Austria) of the extracranial carotid arteries, bilaterally without nephritis compared with healthy controls and [24]. The whole imaging and quantification procedure was this reduction in fetuin-A level was significantly more performed digitally at the time of study entry by a single marked in LN patients compared with SLE patients investigator blinded for clinical data. The measurements without nephritis. The Calcification Risk Index (CRI) of IMTs were performed at four points of both common was significantly higher in SLE patients compared carotid arteries ~10 mm proximal to the carotid bulb, to healthy controls and more marked elevations were avoiding areas of atherosclerotic plaque formation. The found in LN patients. We found significantly increased mean of the resulting eight single measurements was IMT in SLE patients compared with healthy controls taken as mean IMT for statistical analyses in this study. but no significant difference between SLE patients with The ABI was detected by simultaneous measurement of and without LN. Peripheral arterial disease (PAD) was the brachial and posterior tibial artery systolic pressure detected in significantly more patients with LN than SLE [25], using the 5 MHz Mini Dopplex® doppler device patients without nephritis (30% vs. 55%; P < 0.001), (Huntleigh Diagnostic Products, Cardiff, UK). Pressure while no PAD were found in any of the control subjects. was taken at the posterior tibial artery only and the ratio Only one case of mediasclerosis (ABI > 1.3) was detected of ABI from both sides was taken for analyses. Patients in the group of LN patients. were further classified to have prevalent peripheral arterial Correlation studies and their significance levels are disease (PAD) (ABI < 0.9), no PAD (ABI 0.9-1.3), or presented in Table-2. Significant negative correlations mediasclerosis (ABI > 1.3). were observed between fetuin-A levels and serum All data were expressed as mean ± SD. Statistical analyses creatinine, SLEDAI, hsCRP, CRI, IMT and ABI in were performed using the SPSS® 15.0 software package SLE patients with and without LN. The IMT showed (SAS Institute Inc., NC, USA). Analysis of variance was significant positive correlations with CRI and hsCRP in used to estimate the difference between means. Student-t SLE patients with and without lupus nephritis. The ABI test was used to compare two independent means, and showed significant positive correlations with CRI in SLE Chi-square test was used to compare categorical variables. patients with and without LN. The correlation between clinical and biochemical parameters was calculated using Pearson’s correlation Discussion coefficient. P value < 0.05 was considered statistically Among persons with ESRD, vascular calcification has significant. emerged as a powerful and potentially modifiable risk factor of all-cause mortality [26]. Mortality from atherosclerosis Results may be up to 10 times greater in patients with SLE than The clinical and laboratory characteristics of patient in age- and sex-matched controls [6]. Fetuin-A, a potent groups and control subjects are summarized in Table-1. systemic inhibitor of soft tissue calcification, has been There were no significant differences between groups negatively related to VCs and cardiovascular mortality in regarding their age, sex, body mass index (BMI), or dialysis patients [13]. Serum concentrations of fetuin-A Arab Journal of Nephrology and Transplantation 13 Abdel-Wahab, Fathy and Al-Harizy Table-1: Clinical data, diagnostic indices, and blood biochemical analysis for SLE patients without LN, with LN and healthy controls. SLE without LN LN Controls Clinical data (n = 20) (n = 20) (n = 20) Age (years) 25.6 ± 4.1 28.3 ± 4.6 29.2 ± 5.4 BMI (kg/m2) 26.9 ± 5.4 31.2 ± 7.5 28.1 ± 4.5 Systolic blood pressure (mmHg) 127 ± 24 154 ± 37*$ 122 ± 21 Diastolic blood pressure (mmHg) 76 ± 18 98 ± 21 *$ 73 ± 15 Duration of SLE disease (years) 5.2 ± 1.5 5.9 ± 1.8 - Drugs used: Current steroids 16/20 13/20 - Former steroids 4/20 7/20 - Immunosuppressives - 11/20 - SLE Disease Activity Index (SLEDAI) 23.6±5.7 28.9±7.1 $ - Blood Urea Nitrogen (mg/dL) 37.2±11.4 183.5±34.1 *$ 25.1±6.1 Serum Creatinine (mg/dL) 1.2±0.3 3.9±1.1*$ 0.8±0.2 hsCRP (mg/L) 2.4±0.6* 4.1±0.8*$ 1.3±0.4 C3 Complement Level (g/L) 81.4±21.5* 75.8±16.9* 129.4±28.0 Triglycerides (mg/dL) 162.6±24.1 * 171.5±29.3 * 134.6±18.7 Total Cholesterol (mg/dL) 184.4±36.9 * 198.5±31.2 * 155.3±27.6 HDL–Cholesterol (mg/dL) 33.2±8.1 * 31.2±7.4 * 42.7±8.9 LDL–Cholesterol (mg/dL) 108.5±21.5 * 117.4±26.8 * 93.6±19.3 Calcium (mg/dL) 9.8±1.4 * 9.3±1.3 * 8.6±1.1 Inorganic Phosphate (mg/dL) 3.7±0.7 * 4.5±0.9 *$ 3.1±0.6 Calcification Risk Index (CRI) 67.2±9.3* 89.1±12.1 *$ 34.2±6.2 Fetuin–A (g/L) 0.54±0.1* 0.47±0.1*$ 0.78±0.2 Intima–Media Thickness (IMT, mm) 0.6±0.3* 0.8±0.3* 0.3±0.1 Peripheral Arterial Disease (ABI < 0.9) 6/20 (30%) * 11/20 (55%) *$ 0/20 (0%) Values are presented as mean ± SD or proportions. * significant change as compared to healthy controls. $ significant change as compared to SLE patients without nephritis. are depressed in patients with ESRD, and lower serum Current results showed that LN patients have significantly concentrations were independently associated with risk of higher blood pressure, serum creatinine, BUN and cardiovascular and all-cause mortality in this population SLEDAI score, which are expected to be associated with [27]. Also, serum fetuin-A levels were found to be lower active kidney affection. SLE patients with or without LN in SLE patients and its level correlates with disease showed significantly high levels of TG, total cholesterol, activity [22]. Whether serum fetuin-A concentrations are LDL, but low levels of HDL, as compared to healthy associated with kidney function, and whether the protein controls. These results are in accordance with those acts as a key calcification inhibitor in mild-to-moderate reported by Thomas et al [1], stating that SLE patients CKD such as LN, is unknown. Yet, associations of novel exhibit an atherogenic lipid profile characterized by biomarkers such as fetuin-A with metabolic markers or elevated TG and VLDL, with reduced HDL. This form complications do help in understanding their role in the of dyslipidemia is attributed to the interplay between pathophysiology of vascular disease. multiple disease parameters. For instance, elevated levels Arab Journal of Nephrology and Transplantation 14 Fetuin-A and Vascular Disease in SLE Table-2: Correlation coefficients and significance levels among clinical indexes and blood biochemical parameters in SLE patients with and without LN. SLE without LN SLE with LN R P R P Fetuin–A (g/l) Serum creatinine (mg/dL) – 0.68 < 0.001 – 0.74 < 0.001 SLE Disease Activity Index (SLEDAI) – 0.49 < 0.01 – 0.61 < 0.01 hsCRP (mg/dL) – 0.47 < 0.01 – 0.35 < 0.05 Calcification Risk Index (CRI) – 0.83 < 0.001 – 0.88 < 0.001 Intima–Media Thickness (IMT, mm) – 0.57 < 0.01 – 0.70 < 0.001 Ankle–Brachial index (ABI) – 0.62 < 0.001 – 0.59 < 0.01 Intima-Media Thickness (IMT, mm) Serum creatinine (mg/dL) 0.17 > 0.05 0.38 < 0.05 SLE Disease Activity Index (SLEDAI) 0.36 < 0.05 0.26 > 0.05 hsCRP (mg/dL) 0.47 < 0.05 0.63 < 0.01 Calcification Risk Index (CRI) 0.52 < 0.01 0.58 < 0.01 Ankle–Brachial index (ABI) 0.25 > 0.05 0.09 > 0.05 Ankle-Brachial index (ABI) Serum creatinine (mg/dL) 0.30 > 0.05 0.54 < 0.01 SLE Disease Activity Index (SLEDAI) 0.21 > 0.05 0.16 > 0.05 hsCRP (mg/dL) 0.06 > 0.05 0.15 > 0.05 Calcification Risk Index (CRI) 0.78 < 0.001 0.69 < 0.001 of interleukin–1 and interferons have been reported significantly higher in SLE patients, and the increase was to suppress lipoprotein lipase activity [28], and in turn significantly more marked in patients with LN, reflecting reduce the catabolism of TG-rich VLDL and subsequent the active inflammatory condition. Complement C3 formation of LDL. Steroid therapy further elevates TG levels were significantly lower in all SLE patients with levels; possibly through a similar effect on lipoprotein and without LN, compared with the control group. These lipase activity or by promoting insulin resistance [29]. results are in line with the observations by Grevink et These disturbances, alongside the pro-inflammatory, pro- al [33], stating that complement factors facilitate the oxidative state shown to exist in SLE, add up to enhance clearance of apoptotic cells and, when decreased, might the atherogenic propensity in SLE. result in an increased amount of apoptotic cells, such as those found in SLE patients. In fact, low levels of one or In addition to the atherogenic lipid profile, autoantibodies more complement factors, due to increased catabolism, are also thought to play a major role in SLE-related are found in the majority of patients with SLE. atherogenesis, especially those directed against apolipoprotein H and against the endothelium [30]. In our study, calcium and inorganic phosphate levels The latter are of particular interest clinically because of were significantly higher in SLE patients compared with their direct, relation to endothelial apoptosis observed in healthy controls. LN patients showed less elevation of SLE [31]. The immune complexes deposited in vascular calcium, but more elevation of phosphate levels compared walls at sites of vascular injury activate the complement to SLE patients without nephritis. Fetuin-A levels were pathway which, in turn, evokes further inflammatory and significantly lower and calcification risk index (CRI) autoimmune responses that accelerate atherogenesis and was higher in SLE patients, and these changes were vascular calcification [32]. The levels of hsCRP were more marked in patients with LN. Mehrotra et al [27] Arab Journal of Nephrology and Transplantation 15 Abdel-Wahab, Fathy and Al-Harizy observed higher serum concentrations of fetuin-A among non–traditional risk factors as the most probable reason patients with advanced diabetic nephropathy (CKD behind the high prevalence of atherosclerosis in SLE stages 1 to 4) as compared with persons with diabetes patients [39]. However, recent studies showed a strong but without kidney disease. Osawa and colleagues association between fetuin-A levels and events of CVD. [34] reported no association between serum fetuin-A Weikert et al [40] obtained a significantly increased concentrations and total and albumin-corrected calcium, risk for myocardial infarction and ischemic stroke for and an inverse correlation with serum phosphorous individuals in the highest compared with the lowest concentrations among healthy Japanese volunteers quintile of fetuin-A in a model adjusted for cardiovascular without kidney disease. In an unadjusted analysis, Ix et risk factors including age, sex, diabetes, BMI, HDL, al [12] found that higher serum fetuin-A concentrations and hsCRP. Also, Fisher et al [41] have suggested that were associated with higher serum calcium and fetuin-A and fetuin-A gene polymorphisms may play phosphorous concentrations, independent of kidney a causal role in the pathophysiology of atherosclerosis function. Fetuin-A, a binder/carrier of serum calcium– leading to CV events. phosphate, stabilizes the concentration of serum calcium Contradictory results have also been published regarding and prevents its precipitation. It promotes phagocytosis the role of fetuin-A in macrovascular disease in patients of redundant calcium and thus, it is regarded as a potent with type-2 diabetes. While some studies associated circulating inhibitor of cardiovascular calcification [35]. lower fetuin-A levels with peripheral arterial disease The present study showed the existence of significant (PAD) [25], others observed an association of increased correlations between low fetuin-A levels and serum fetuin-A levels with coronary artery calcification [27, creatinine, SLEDAI, CRI, IMT and ABI in SLE patients, 42]. Estimation of the ankle-brachial index (ABI) in with and without nephritis. Low serum fetuin-A levels this study detected peripheral arterial disease (PAD) in were previously observed in SLE patients and were significantly more LN patients than SLE patients without found to correlate with SLEDAI and IMT [22]. Mori et nephritis. This correlated significantly with CRI, but al [36] reported that feutin-A levels are related to carotid correlated negatively with serum fetuin-A levels. ABI arterial stiffness, regardless of the nature of contributing also correlated significantly with serum creatinine in atherogenic factors. LN patients. These findings support the hypothesis that In young population with mild-to-moderate alterations in low fetuin-A might result in vascular calcification. Also, renal function and with less traditional cardiovascular risk Eraso et al [25] found that patients with type-2 diabetes factors, Kanbay et al [14] observed small modifications and PAD have lower levels of fetuin-A than patients in serum levels of fetuin-A early in the course of disease with type-2 diabetes alone. However, Lorant et al [42] evolution that can predict the extent of coronary artery demonstrated that patients with type-2 diabetes who disease. Ketteler et al [21] demonstrated that lower additionally suffer from PAD have significantly higher fetuin-A concentrations were independently associated fetuin-A levels than patients with diabetes but without any with cardiovascular and all-cause mortality in dialysis atherosclerotic burden. Low fetuin-A was also associated patients. These results were recently confirmed in incident with mediasclerosis in patients with diabetes and PAD. hemodialysis and peritoneal dialysis patients [37]. As The role of fetuin-A and its involvement in atherosclerosis fetuin-A is a potent inhibitor of vascular calcification seems to be very complex and is not yet understood. and as low levels had been associated with coronary Atherosclerotic plaques, in general, provoke fibrosis artery and valvular calcification [38], the hypothesis was and vascular calcification, which is a marker of generated that the excess mortality risk observed in these increased vulnerability to cardiovascular events and studies may have been due to accelerated cardiovascular mortality. Reduced fetuin-A levels are associated with calcification among ESRD patients with lower serum inflammation and increased cardiovascular calcification concentrations of fetuin-A. Our results indicated (CVC) [43]. In experimental mice with kidney disease significantly increased IMT of carotid arteies in SLE that were provided high phosphate feeding, wild-type patients and this was more marked in LN patients. The mice developed high serum calcium and phosphorous IMT had significant positive correlations with CRI and levels, but did not develop extra-osseous calcification. In hsCRP, but significant negative correlations with fetuin-A contrast, fetuin-A knockout mice developed significant levels. These observations seem to fall in accordance soft tissue calcification while maintaining normal serum with the findings of other investigators who pointed to calcium and phosphorous levels [44]. These findings Arab Journal of Nephrology and Transplantation 16 Fetuin-A and Vascular Disease in SLE suggest that under certain conditions, elevated serum High levels by associations with metabolic syndrome concentrations of calcium and phosphorus may reflect and atherogenic lipids result in CVD and low levels by improved ion solubility. The presence of pre-existing associations with vascular calcification also result in CVD and alterations in mineral metabolism conferred CVD. by CKD may have led to the up-regulation of fetuin-A in association with elevated calcium and phosphorous A point worthy emphasis in this study is the effect of levels, perhaps to offset the propensity towards dystrophic medication on lupus-associated atherosclerosis. All mineralization [12]. Structure–function studies have patients used steroids treatment during the course of the suggested that fetuin-A solubilizes calcium phosphate disease; most of them were current users of steroids in a crystals by direct and reversible binding, reminiscent dose range of 20 to 60 mg/day. More than half the patients of the process in which apolipoproteins solubilize lipids with LN used immunosuppressive treatment, in addition in solution [45]. In humans so far the available data has to steroids. Corticosteroid therapies have been shown been inconsistent. Lower fetuin-A levels are associated to have adverse effects on the traditional risk factors with mortality and coronary vascular disease events in cohorts with ESRD [26], while a population based study of atherosclerosis such as blood pressure, lipid profile, linked high plasma fetuin-A levels to an increased risk obesity, and blood glucose level [29]. Although there is of myocardial infarction and ischemic stroke [40]. Yet, very little dispute about the beneficial anti–inflammatory no association could be detected between fetuin-A, and effect of corticosteroid therapy, there seems to be, a traditional cardiovascular risk factors, cardiovascular disagreement about the criteria defining an ‘adequate’ outcome or the metabolic syndrome in patients with corticosteroid dose. Several investigators suggested manifest CHD in a 6-year follow up study [46]. Our that, as far as SLE patients are concerned, corticosteroid results detected an inverse correlation between serum doses are considered sufficient only if they are enough to fetuin-A levels and hsCRP levels in SLE patients with prevent premature atheromatosis [48]. Certain findings in and without LN. However, Hennige et al [47] found a positive correlation between circulating fetuin-A and this study may add some justification to that approach as hsCRP, a systemic marker of subclinical inflammation. it was observed, by comparing the patient’s histories, that Contrariwise to renal dialysis patients, several studies patients with increased IMT always had less prednisone showed that high levels of fetuin-A were associated medication, in both frequency and dose. with atherosclerosis and its manifestations in non-renal A relative strength of our study is the availability of patients [40]. This possible involvement of fetuin-A in the pathogenesis of cardiovascular disease has been several parameters of kidney function and measurement confirmed by a recent trans-European cohort study of multiple potential risk factors for vascular disease. with 2,520 patients [41]. Thus, it seems that high levels However, there are several limitations that should be of fetuin-A are associated with atherosclerosis and its considered when interpreting our results. Our study manifestations in non-renal patients. could not evaluate the association of advanced CKD and Because those studies were cross-sectional, it is not serum fetuin-A. For now, the mechanisms explaining impossible that fetuin-A had detrimental effects on the the association between CKD and vascular calcification vasculature. It is possible that fetuin-A is upregulated remain elusive. Whether a threshold of kidney function to protect against calcification but deteriorates exists, at which fetuin-A concentrations decline cannot be atherosclerosis [12]. Nevertheless, patients with media addressed in our study sample. A better understanding of artery sclerosis showed significantly lower levels of the regulation of fetuin-A in the presence and absence of fetuin-A. This is in line with the calcification inhibition uremia and vascular disease and at varying concentrations competence of fetuin-A [42]. It is to be noted that, in the of calcium and phosphorus is required. The cross-sectional past few years, many biological parameters in humans design of our study does not allow for causal inference or were shown to follow not a simple linear association, but a U-shaped relationship (such as BMI, hemoglobin). evaluation of direction of associations. Finally, our study Ix et al [12] suggested a U-shaped relationship also for participants were all females and had SLE; and therefore fetuin-A values with CVD. They considered either high results may not be generalizable to men or to persons or low levels of fetuin-A to predict cardiovascular events. without SLE disease. Arab Journal of Nephrology and Transplantation 17 Abdel-Wahab, Fathy and Al-Harizy Conclusion targeted deletion of the mouse fetuin gene. J Biol Chem. 1997 Dec 12;272(50):31496-503. In conclusion, fetuin-A levels were decreased in SLE patients with and without LN and these levels were 12. Ix JH, Chertow GM, Shlipak MG, Brandenburg inversely correlated with vascular complications. VM, Ketteler M, Whooley MA. 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