CLINICAL INVESTIGATION
Metabolic Syndrome Is Correlated With Carotid Atherosclerosis in Patients With Lupus Nephritis Minfang Zhang, MD, Chaojun Qi, MD, Liou Cao, MD, Jiaqi Qian, MD and Zhaohui Ni, MD
Abstract: Background: To investigate the prevalence of metabolic syndrome (MS) in patients with lupus nephritis (LN), and its correlation with carotid atherosclerosis. Methods: Two hundred ten patients with LN (age: 38.83 6 12.41 years, 92.86% women) were enrolled. The control group included 150 lupus patients without nephritis and 200 age-matched healthy persons. The improved criteria in 2009 were used to calculate the prevalence of MS, and carotid artery ultrasound was used to detect plaque and intima-media thickness (IMT). The correlation between MS and carotid atherosclerosis in patients with LN was analyzed. Results: The prevalence of MS in patients with LN was 41.90%, which was significantly higher than that in lupus patients without nephritis (30.67%) and healthy controls (11.50%). LN patients with MS showed a significantly increased carotid plaque ratio (28.41% versus 17.21%, P , 0.05) and IMT value (0.74 6 0.25 mm versus 0.64 6 0.18 mm, P , 0.01). Stepwise multiple regression further confirmed that age (b 5 0.026, P 5 0.033), duration of disease (b 5 0.057, P 5 0.025) and MS (b 5 0.074, P , 0.001) were independent risk factors that affected the carotid IMT value in patients with LN. Conclusions: The prevalence of MS was comparatively high in patients with LN and was significantly correlated with carotid atherosclerosis, indicating that MS screening might be useful in the prevention and treatment of carotid atherosclerosis in patients with LN. Key Indexing Terms: Metabolic syndrome; Lupus nephritis; Atherosclerosis. [Am J Med Sci 2014;348(6):486–491.]
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ystemic lupus erythematosus (SLE) is an autoimmune inflammatory disease involving multiple organs; twothirds to three-fourths of patients with SLE develop renal damage. Several studies reported that the prevalence and mortality rates of cardiovascular disease (CVD) in patients with lupus nephritis (LN) were significantly higher than in healthy persons.1,2 As immunosuppressive treatment gradually becomes more sophisticated, the mortality rate of acute-phase patients has decreased significantly, whereas CVD has become the main cause of death among patients with LN in the stable phase.3 Carotid artery ultrasound is a simple and reliable method used to detect subclinical atherosclerosis in the early stages. Carotid artery plaque and intima-media thickness (IMT) are easy to test noninvasively and thus can be used as windows to observe atherosclerosis development in the entire body.4 Recent studies have shown that metabolic syndrome (MS) is closely correlated with the occurrence and prognosis of CVD. Every component of MS is a risk factor of CVD occurrence, and a combination of multiple abnormalities occurring at the same time results in a higher CVD risk.5 Although a consensus has not been reached in terms of the exact definition of MS among different periods and academic From the Renal Division, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. Submitted March 4, 2014; accepted in revised form July 9, 2014. Supported by the Seed Research Program of Shanghai Renji Hospital. The authors have no financial or other conflicts of interest to disclose. Correspondence: Zhaohui Ni, MD, Renal Division, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai 200127, China (E-mail: [email protected]).
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organizations, the improved criteria of MS established by the International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute in 2009 are widely recognized by academia at present.6 The criteria state that a diagnosis can be made if either 3 of the following are present: central obesity, increased triglycerides (TG), decreased high-density lipoprotein cholesterol (HDL-C), increased blood pressure and increased fasting blood glucose (FBG). In the general population, as well as in adolescents and adults with hypertension, MS was previously reported to be correlated with carotid atherosclerosis.7–9 However, no relevant report was found in patients with LN. Hence, in this observational study, we performed carotid artery ultrasound on patients with LN and discussed its relevance in the prevalence of MS.
METHODS Study Subjects This was a single-center, cross-sectional study. Two hundred ten SLE patients with LN, who visited our hospital between January 2010 and October 2013, were selected as study subjects. The control group included 150 age-matched SLE patients without nephritis and 200 age-matched healthy persons. We referred to the diagnostic criteria for SLE classification established by the American Rheumatism Association.10,11 The exclusion criteria were as follows: (1) acute cardiovascular events (defined as acute coronary syndrome, new-onset arrhythmia, heart failure, cerebrovascular accident, peripheral vascular thrombosis or arterial dissection, etc.) occurring within a month before selection, (2) infection or trauma occurring within a month before selection, (3) tumors, (4) familial hyperlipidemia, (5) pregnancy or childbirth in women, (6) acute exacerbation of chronic renal failure and (7) dialysis or renal transplant. Disease activity was evaluated using the SLE disease activity index.12 Therapeutic exposures including corticosteroid, immunosuppressant and antimalarial drugs were recorded. All corticosteroid doses were converted to milligrams of prednisolone equivalent. The cumulative dose of prednisolone received from the beginning of treatment to enrollment (in grams) was calculated for each patient. The procedures followed in the study meet ethical requirements and were approved by the ethics committee of our hospital. All participants gave informed consent. Diagnostic Criteria of Metabolic Syndrome This study used the 2009 improved criteria of MS, which require meeting 3 or more of the following 5 components: (1) central obesity: waist circumference $90 cm in Chinese males and $80 cm in females (for a few patients without waist circumference data, body mass index [BMI] $25 kg/m2 was used instead), (2) increased TG: $150 mg/dL (1.7 mmol/L), or already receiving appropriate treatments, (3) decreased HDL-C: ,40 mg/dL (1.0 mmol/L) in males and ,50 mg/dL (1.3 mmol/L) in females, or already receiving appropriate treatments, (4) increased blood pressure: systolic blood pressure (SBP) $130 mm Hg, diastolic blood pressure (DBP) $85 mm Hg, already receiving appropriate
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MS and Carotid Atherosclerosis in Patients With LN
treatments or with a previous diagnosis of hypertension and (5) increased FBG: $100 mg/dL (5.6 mmol/L), a previous diagnosis of type 2 diabetes, or already receiving appropriate treatments. The “number of MS components” refers to the total number of aforementioned components in each patient, ranging from 0 to 5. Physical and Laboratory Examinations In all patients, blood pressure was measured in the morning, with the patient in the supine position after resting for at least 10 minutes. A mercury sphygmomanometer was used with the band wrapped on the left upper arm at the level of the heart. After blood pressure measurement, the height and weight of the patient were measured to calculate BMI. Waist circumference was measured from the front of the body, at the thinnest point between the ribs and the hipbone after exhalation. Fasting blood samples were drawn to test the following indices: hemoglobin, erythrocyte sedimentation rate, creatinine, urea nitrogen, uric acid, albumin, total cholesterol, TG, HDL-C, lowdensity lipoprotein cholesterol, FBG, calcium, phosphorus, complements C3 and C4, fibrinogen, high-sensitivity C-reactive protein (hs-CRP) and antibody test. hs-CRP was tested by using rate nephelometry (BNP nephelometer; Dade Behring, Deerfield, IL). The titer of serum antibodies against double-stranded DNA (ds-DNA) was determined by using radioimmunoassay (EUROIMMUN AG, Germany). Anti-nuclear antibody (ANA) was detected by using an indirect immunofluorescence method. Anti-cardiolipin antibody (ACL) was determined by using an enzyme-linked immunosorbent assay (EUROIMMUN AG, Leubeck, Germany). Twenty-four-hour urine samples were collected for quantitative examination of urinary proteins. Glomerular filtration rate (GFR) was calculated by using the following equation: 186 3 (Scr/88.4)21.154 3 age20.203 3 (0.742 if female).13 Carotid Artery Doppler Ultrasound Carotid artery ultrasound examinations were performed by professional sonographers at our hospital. The intervals between examination and blood sampling were controlled to be no more than 1 month. An HP-HX Color Doppler Ultrasound Diagnostic System (Hewlett-Packard Company, Palo Alto, CA) was used, with the transducer frequency at 10 MHz, the angle between ultrasonic beam and blood flow kept at ,60° and carotid artery IMT measured at 2 cm from the carotid bifurcation. IMT was defined as the distance from the interface between the tunica adventitia and media to the intimal surface. Atherosclerotic plaque was defined as local intima, that is, thicker than 1 mm and more than twice the thickness of the adjacent intima.14 Systolic peak velocity, diastolic velocity and resistance index were also measured. Statistical Methods Measurement data were expressed as mean 6 SD or median (interquartile range). Independent 2-sample t test was used to compare differences between 2 sets of data that are normally distributed. One-way analysis of variance was used to compare differences between multiple sets of data. MannWhitney’s U test was used to compare differences between 2 sets of data that are not normally distributed. A x2 test was used to compare differences in composition ratios. Pearson’s method was used for correlation analysis. Stepwise multiple linear regression was used to analyze the relation between 1 dependent variable and multiple independent variables. SPSS 19.0 software was used for statistical analysis. P , 0.05 was considered statistically significant. Ó 2014 Lippincott Williams & Wilkins
RESULTS Baseline Data The 210 patients with LN included 195 female patients (92.86%), and their average age was 38.83 6 12.41 years. Among them, 202 patients (96.19%) were ANA positive, 186 patients (88.57%) were ds-DNA positive and 40 patients (19.05%) were ACL antibody positive. One hundred fiftyeight patients (75.24%) had undergone renal biopsy; according to the 2003 LN classification by the International Society of Nephrology/Renal Pathology Society,15 there were 4 cases (2.53%) of minimal mesangial lesions (class I), 9 cases (5.70%) of mesangial proliferative lesions (class II), 21 cases (13.29%) of focal lesions (class III), 86 cases (54.43%) of diffuse lesions (class IV), 35 cases (22.15%) of membranous lesions (class V) and 3 cases (1.90%) of advanced sclerosis lesions (class VI). There was no significant difference regarding age and sex ratio among patients with LN, SLE patients without LN and healthy controls. The duration of disease and SLE disease activity index score were similar in SLE patients with LN and without LN. Prevalence of Carotid Artery Plaque Plaques were detected in 46 patients with LN (21.90%), 24 patients with SLE (16.00%) and 13 healthy controls (6.50%). The prevalence of carotid artery plaque was significantly higher in patients with LN compared with that in patients with SLE (P , 0.05) and healthy controls (P , 0.01). The patients with LN were divided into 2 groups according to the existence of carotid artery plaque. Compared with the nonplaque group, LN patients with plaques were older, had longer durations of disease, had higher BMI, had higher levels of SBP, FBG, TG, CRP and uric acid and had significantly decreased levels of hemoglobin and GFR. No significant difference was found regarding disease activity and medication between the 2 groups (Table 1). Prevalence of Metabolic Syndrome Eighty eight patients (41.90%) with LN, 46 patients (30.67%) with SLE and 23 (11.50%) healthy controls were diagnosed with MS. The prevalence of MS was significantly higher in patients with LN compared with that in patients with SLE (P , 0.05) and healthy controls (P , 0.01). The characteristics of LN patients with and those without MS were compared, and the results are shown in Table 2. LN patients with MS were older, had longer durations of disease, had higher BMI, waist circumference and cumulative dose of corticosteroid, had higher levels of SBP, DBP, CRP, FBG and TG and had lower levels of GFR and HDL-C. The sex ratios, albumin and urine protein levels, disease activity and positive rates of autoantibodies, including ds-DNA, ANA and ACL, showed no significant difference between the 2 groups. Correlation Between Metabolic Syndrome and Carotid Atherosclerosis in Patients With LN The carotid artery plaque ratio (28.41% versus 17.21%, P , 0.05) and IMT value (0.74 6 0.25 mm versus 0.64 6 0.18 mm, P , 0.01) were significantly elevated in LN patients with MS, as shown in Figure 1. In addition, as the number of MS components increased, the IMT value of the carotid artery in patients with LN showed a gradual upward trend (P , 0.01), as shown in Figure 2. In the univariate analysis, variables that were linearly correlated with carotid artery IMT, including age, duration of disease, BMI, SBP, FBG, TG, uric acid, CRP, GFR and cumulative dose of corticosteroid as well as the presence or absence of MS, were all included in stepwise
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TABLE 1. Comparison between LN patients with and without carotid artery plaque With plaque Without plaque (n 5 46) (n 5 164) Age, y 42.15 6 15.92 33.95 6 11.84a Gender, male, % 8.93 8.16 BMI, kg/m2 23.28 6 3.85 20.95 6 2.96b Waist circumference, 75.24 6 18.35 74.06 6 13.30 cm Smoke history, % 10.65 11.93 Duration of LN, mo 68.00 (17.00–108.00) 42.00 (19.25–70.75)a SBP, mm Hg 148.34 6 18.25 135.92 6 14.92b DBP, mm Hg 82.14 6 9.23 80.62 6 8.31 MABP, mm Hg 104.42 6 12.14 101.01 6 10.95b FBG, mmol/L 5.03 6 0.84 4.28 6 0.62b Hemoglobin, g/dL 96.62 6 22.99a 109.95 6 22.43b ESR, mm/h 58.00 (24.00–87.00) 47.00 (24.00–75.00) hs-CRP, mg/L 3.64 (2.03–5.84) 1.57 (0.89–2.38)a 21 GFR, mL$min $1.73 78.74 6 6.21 90.15 6 8.33a m22 Uric acid, umol/L 491.78 6 29.35 408.21 6 20.56b Calcium, mmol/L 2.08 6 0.28 2.06 6 0.24 Phosphate, mmol/L 1.29 6 0.37 1.25 6 0.22 TC, mmol/L 4.65 6 0.92 4.62 6 0.98 TG, mmol/L 1.66 (1.08–2.05) 1.42 (1.01–1.79)a LDL-C, mmol/L 2.59 6 0.88 2.71 6 0.86 HDL-C, mmol/L 1.14 6 0.32 1.28 6 0.41 Albumin, g/L 37.64 6 4.06 38.58 6 4.74 24-h urine protein, 3.48 6 2.91 3.07 6 2.52 g/24 h ds-DNA, % 89.54 88.40 ANA, % 95.94 97.25 ACL, % 19.86 18.32 Complement C3, g/L 0.64 (0.48–0.93) 0.58 (0.47–0.75) Fibrinogen, g/L 3.68 6 1.38 3.79 6 1.31 SLEDAI 4 (2–6) 5 (0–8) Medication Current use of CS, % 80.43 79.26 Current dose of CS, 5 (0–10) 8 (0–15) mg/d Cumulative dose of 12.25 (4.60–20.15) 8.80 (2.75–16.50) CS, g Immunosuppressant, % 34.78 31.70 Antimalarial, % 52.17 51.83 P , 0.01. P , 0.05. CS, corticosteroid; ESR, erythrocyte sedimentation rate; LDL-C, low-density lipoprotein cholesterol; MABP, mean arterial blood pressure; TC, total cholesterol. a b
multiple linear regression equation, and the results showed that age (b 5 0.026, P 5 0.033), duration of disease (b 5 0.057, P 5 0.025) and the presence of MS (b 5 0.074, P , 0.001) were independent risk factors that affected the carotid IMT value in patients with LN (Table 3).
DISCUSSION We found in our cross-sectional study that among patients with LN, those with MS had significantly increased carotid artery plaque ratio and IMT value, and that MS was an
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independent risk factor that affected the IMT levels of patients with LN. The independent correlation between MS and carotid atherosclerosis is consistent with the results of previous studies in normal populations, and the results of this study have expanded this claim to include the LN population. This is of great importance in clarifying the risk stratification for CVDs in patients with LN. Many studies have shown that the risk of CVD occurrence in patients with SLE is significantly higher than in healthy persons from the same age groups. In 1976, Urowitz et al16 proposed a bimodal mortality pattern: patients with early SLE mostly died of lupus activity and infection, whereas patients with late SLE mainly died of atherosclerosis-related diseases. Autopsy revealed that moderate to severe aortic, coronary, cerebral and renal atherosclerosis was present in 41% to 53% of patients with SLE.17 The reasons for atherosclerosis occurrence in patients with SLE are extremely complex. Conventional risk factors such as age, family history and smoking play important roles, yet cannot completely explain the increased CVD occurrence rate.18 SLE itself is a risk factor for atherosclerosis: various autoantibodies and sensitized lymphocytes against self-antigens existing in the bodies of patients with SLE facilitate the entrance of monocytes into blood vessel walls, which activate endothelial cells and cause the formation of atherosclerosis.19 It was previously reported that the longer the duration of SLE, the higher the possibility for the occurrence of CVD events.20 Our study also confirmed that patients with LN with long disease durations have a high occurrence rate of carotid atherosclerosis. Therapeutic exposure is another important reason for atherosclerosis in SLE duration. It is well known that long-term use of corticosteroids not only causes several metabolic disorders but also increases the risk of CVD. MS is a clinical syndrome that involves a combination of multiple metabolic diseases, including central obesity, hyperglycemia, dyslipidemia and hypertension. It is a combination of a group of metabolically correlated risk factors. This series of factors may directly promote the occurrence of atherosclerotic CVDs.21 In our study, the MS occurrence rate observed in patients with LN was 41.90%, which was significantly higher than that in patients with SLE and healthy controls. Compared with lupus patients without nephritis, LN is associated with more physiological and metabolic disturbances, including proteinuria, hypertension, dyslipidemia, insulin resistance and decreased GFR which are linked to increased risk of carotid atherosclerosis. Several hormonal, inflammatory and nutritional-metabolic factors may play key roles in MS development in kidney disease, such as raised proinflammatory cytokines, hyperactivation of the renin-angiotensin aldosterone system (RAAS), abnormal adipocytokine levels and poor vitamin D status.22 Obesity and insulin resistance are initiating factors of MS occurrence. The RISC study found through 3 years of followups that obesity is closely related with impaired insulin sensitivity and is independent of other variables.23 Furthermore, abdominal (visceral) obesity is a sign of insulin resistance. Our study found that the obesity index, BMI, in patients with LN of the MS group was significantly higher than that of the non-MS group, and the waist circumference value, which represents abdominal obesity, showed a significant difference. Since visceral fat cells metabolize more actively than subcutaneous fat cells, persons with abdominal obesity produce more free fatty acid, which causes lipid deposition in nonadipose tissues such as the liver and muscle. This will result in decreased insulin sensitivity in these tissues, which can trigger insulin resistance.24 Volume 348, Number 6, December 2014
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TABLE 2. Comparison between LN patients with and without MS With MS Without MS (n 5 88) (n 5 122) Age, y 41.39 6 10.83 35.72 6 12.05a Gender, male, % 8.75 8.85 BMI, kg/m2 23.84 6 4.25 20.37 6 3.14b Waist 77.48 6 16.28 71.96 6 15.98b circumference, cm Smoke history, % 11.23 10.77 Duration of LN, mo 65.00 (18.25–105.75) 44.00 (18.00–72.00)a SBP, mm Hg 150.37 6 20.21 132.75 6 16.89b DBP, mm Hg 87.28 6 11.29 79.52 6 9.93b MABP, mm Hg 109.84 6 15.36 102.74 6 12.80b FBG, mmol/L 4.87 6 0.72 4.14 6 0.66b Hemoglobin, g/dL 99.46 6 19.57b 102.76 6 21.82 ESR, mm/h 49.00 (26.00–90.00) 52.00 (21.00–78.00) hs-CRP, mg/L 3.47 (2.12–5.48) 1.66 (0.78–2.49)a 21 GFR, mL$min 79.62 6 7.46 88.65 6 9.05b $1.73 m22 Uric acid, umol/L 446.24 6 30.75 437.95 6 22.12 Calcium, mmol/L 2.03 6 0.19 2.07 6 0.21 Phosphate, mmol/L 1.21 6 0.28 1.28 6 0.23 TC, mmol/L 4.59 6 0.89 4.64 6 0.94 TG, mmol/L 1.63 (1.02–2.11) 1.44 (1.00–1.82)a LDL-C, mmol/L 2.69 6 0.82 2.61 6 0.67 HDL-C, mmol/L 1.01 6 0.23 1.31 6 0.38b Albumin, g/L 38.57 6 3.96 36.90 6 4.15 24-h urine 3.25 6 3.12 3.38 6 2.99 protein, g/24 h ds-DNA, % 87.35 89.93 ANA, % 97.25 95.81 ACL, % 17.96 19.02 Complement C3, g/L 0.59 (0.42–0.86) 0.60 (0.42–0.86) Fibrinogen, g/L 3.75 6 1.35 3.70 6 1.38 SLEDAI 5 (2–7) 4 (2–6) Medication Current use of CS, % 84.09 77.87 Current dose of CS, 10 (0–20) 5 (0–10) mg/d Cumulative dose of 16.50 (6.00–29.50) 7.25 (1.90–18.25)b CS, g Immunosuppressant, % 32.95 34.43 Antimalarial, % 46.59 53.28
FIGURE 1. Comparison of the carotid artery plaque ratio and IMT level between LN patients with and without MS. The carotid artery plaque ratio (28.41% versus 17.21%, P , 0.05) and IMT value (0.74 6 0.25 mm versus 0.64 6 0.18 mm, P , 0.01) were significantly elevated in LN patients with MS.
including adiponectin, resistin and leptin. Studies have revealed that in the presence of MS, metabolic disorders of these adipocytokines can all be involved in insulin resistance, dyslipidemia, abnormal glycometabolism, impaired vascular endothelial function and inflammatory reactions.26 Patients with MS show significantly decreased levels of adiponectin, which has antiinflammatory and antiatherosclerotic effects.27 Thus, obesity and insulin resistance both play important roles in the
P , 0.01. P , 0.05. CS, corticosteroid; ESR, erythrocyte sedimentation rate; LDL-C, low-density lipoprotein cholesterol; MABP, mean arterial blood pressure; TC, total cholesterol. a b
Compensatory hyperinsulinemia caused by insulin resistance can cause reduced antioxidant capacity and systemic inflammation.25 The results of our study indicate that the hsCRP level of patients with LN in the MS group was significantly higher than that of the non-MS group. Changes in the above-mentioned related indices will damage vascular endothelial cells and cause systemic arterial wall damage, which contributes to lipid deposition and causes the occurrence and development of atherosclerosis. In addition, adipose tissue is also an endocrine organ that secretes a series of adipocytokines, Ó 2014 Lippincott Williams & Wilkins
FIGURE 2. Correlation between the number of MS components and IMT level in patients with LN. As the number of MS components increased, the IMT value of the carotid artery in patients with LN showed a gradual upward trend (P , 0.01).
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TABLE 3. Risk factors that affect IMT level of carotid artery in patients with LN Determinants: IMT
Age log (duration of LN) MS
b
R2
P
0.026 0.057 0.074
0.119 0.226 0.194
0.033 0.025 ,0.001
Output from a multivariate stepwise regression model, which showed that MS was an independent marker for IMT. The original model included all variables significantly associated with IMT on univariate analysis, including age, duration of LN, BMI, SBP, FBG, TG, uric acid, CRP, GFR and cumulative dose of corticosteroid and the presence or absence of MS.
occurrence and development of atherosclerosis. Moreover, in the presence of MS, insulin resistance can cause hyperglycemia and increase the activity of the sympathetic nervous system, hinder endothelium-dependent nitric oxide synthesis and release, promote the proliferation of vascular smooth muscle cells, increase vascular resistance and trigger hypertension.28 In this study, LN patients with MS showed higher levels of SBP, DBP and FBG than patients without MS. Furthermore, IMT was positively correlated with SBP in patients with LN. Another important characteristic of metabolic disorder in patients with MS is dyslipidemia. The results of our study show that LN patients with MS have significantly higher TG levels than patients without MS, whereas their HDL-C levels are significantly lower than those of patients without MS. In the presence of MS, LDL particles rich in TG produced by the body become small and dense through lipolysis and can infiltrate more easily into the vessel wall and be oxidized, thus conferring stronger atherosclerotic promotion effects. Furthermore, HDL at low levels acquires a different composition, the core of which is rich in triacylglycerol and has a decreased level of cholesteryl ester, suggesting reduced antioxidant capacity and protective effect.29
CONCLUSIONS In conclusion, we found a correlation between MS and the degree of carotid atherosclerosis in patients with LN. Multiple intervention measures, including lifestyle modification, are recommended for this population to actively correct MS, in an attempt to prevent and control the occurrence and development of atherosclerosis.
ACKNOWLEDGMENTS The authors appreciated all the patients who voluntarily participated in this study. REFERENCES 1. Frostegård J. Systemic lupus erythematosus and cardiovascular disease. Lupus 2008;17:364–7. 2. Scalzi LV, Ballou SP, Park JY, et al. Cardiovascular disease risk awareness in systemic lupus erythematosus patients. Arthritis Rheum 2008;58:1458–64. 3. Gustafsson JT, Simard JF, Gunnarsson I, et al. Risk factors for cardiovascular mortality in patients with systemic lupus erythematosus, a prospective cohort study. Arthritis Res Ther 2012;14:R46.
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4. Nguyen-Thanh HT, Benzaquen BS. Screening for subclinical coronary artery disease measuring carotid intima media thickness. Am J Cardiol 2009;104:1383–8. 5. Wang J, Ruotsalainen S, Moilanen L, et al. The metabolic syndrome predicts cardio-vascular mortality: a 13-year follow-up study in elderly non-diabetic Finns. Eur Heart J 2007;28:857–64. 6. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120: 1640–5. 7. Iglseder B, Cip P, Malaimare L, et al. The metabolic syndrome is a stronger risk factor for early carotid atherosclerosis in women than in men. Stroke 2005;36:1212–7. 8. Reinehr T, Wunsch R, Pütter C, et al. Relationship between carotid intima-media thickness and metabolic syndrome in adolescents. J Pediatr 2013;163:327–32. 9. Cuspidi C, Sala C, Lonati L, et al. Metabolic syndrome, left ventricular hypertrophy and carotid atherosclerosis in hypertension: a genderbased study. Blood Press 2013;22:138–43. 10. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25:1271–7. 11. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725. 12. Bombardier C, Gladman DD, Urowitz MB, et al. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 1992;35:630–40. 13. Zuo L, Ma YC, Zhou YH, et al. Application of GFR-estimating equations in Chinese patients with chronic kidney disease. Am J Kidney Dis 2005;45:463–72. 14. Stompór T, Krasniak A, Su1owicz W, et al. Changes in common carotid artery intima-media thickness over 1 year in patients on peritoneal dialysis. Nephrol Dial Transpl 2005;20:404–12. 15. Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 2004;65:521–30. 16. Urowitz MB, Bookman AA, Koehler BE, et al. The bimodal mortality pattern of systemic lupus erythematosus. Am J Med 1976;60:221–5. 17. Bessant R, Hingorani A, Patel L, et al. Risk of coronary heart disease and stroke in a large British cohort of patients with systemic lupus erythematosus. Rheumatology (Oxford) 2004;43:924–9. 18. Bruce IN, Urowitz MB, Gladman DD, et al. Risk factors for coronary heart disease in women with systemic lupus erythematosus: the Toronto Risk Factor Study. Arthritis Rheum 2003;48:3159–67. 19. Gómez-Zumaquero JM, Tinahones FJ, De Ramón E, et al. Association of biological markers of activity of systemic lupus erythematosus with levels of anti-oxidized low-density lipoprotein antibodies. Rheumatology (Oxford) 2004;43:510–3. 20. Esdaile JM, Abrahamowicz M, Grodzicky T, et al. Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum 2001;44:2331–7. 21. Lionetti L, Mollica MP, Lombardi A, et al. From chronic overnutrition to insulin resistance: the role of fat-storing capacity and inflammation. Nutr Metab Cardiovasc Dis 2009;19:146–52. 22. Slee AD. Exploring metabolic dysfunction in chronic kidney disease. Nutr Metab (Lond) 2012;26:36.
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23. Bobbioni-Harsch E, Pataky Z, Makoundou V, et al. Fat distribution influences the cardio-metabolic profile in a clinically healthy European population. Eur J Clin Invest 2009;39:1055–64.
26. de Ferranti S, Mozaffarian D. The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences. Clin Chem 2008; 54:945–55.
24. Koska J, Stefan N, Permana PA, et al. Increased fat accumulation in liver may link insulin resistance with subcutaneous abdominal adipocyte enlargement, visceral adiposity, and hypoadiponectinemia in obese individuals. Am J Clin Nutr 2008;87:295–302.
27. Calton EK, Miller VS, Soares MJ. Factors determining the risk of the metabolic syndrome: is there a central role for adiponectin? Eur J Clin Nutr 2013;67:485–91.
25. Romeo GR, Lee J, Shoelson SE. Metabolic syndrome, insulin resistance, and roles of inflammation–mechanisms and therapeutic targets. Arterioscler Thromb Vasc Biol 2012;32:1771–6.
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28. Ferrannini E, Cushman WC. Diabetes and hypertension: the bad companions. Lancet 2012;380:601–10. 29. Franssen R, Monajemi H, Stroes ES, et al. Obesity and dyslipidemia. Med Clin North Am 2011;95:893–902.
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Metabolic Syndrome Is Correlated With Carotid Atherosclerosis in Patients With Lupus Nephritis Minfang Zhang, MD, Chaojun Qi, MD, Liou Cao, MD, Jiaqi Qian, MD and Zhaohui Ni, MD
Abstract: Background: To investigate the prevalence of metabolic syndrome (MS) in patients with lupus nephritis (LN), and its correlation with carotid atherosclerosis. Methods: Two hundred ten patients with LN (age: 38.83 6 12.41 years, 92.86% women) were enrolled. The control group included 150 lupus patients without nephritis and 200 age-matched healthy persons. The improved criteria in 2009 were used to calculate the prevalence of MS, and carotid artery ultrasound was used to detect plaque and intima-media thickness (IMT). The correlation between MS and carotid atherosclerosis in patients with LN was analyzed. Results: The prevalence of MS in patients with LN was 41.90%, which was significantly higher than that in lupus patients without nephritis (30.67%) and healthy controls (11.50%). LN patients with MS showed a significantly increased carotid plaque ratio (28.41% versus 17.21%, P , 0.05) and IMT value (0.74 6 0.25 mm versus 0.64 6 0.18 mm, P , 0.01). Stepwise multiple regression further confirmed that age (b 5 0.026, P 5 0.033), duration of disease (b 5 0.057, P 5 0.025) and MS (b 5 0.074, P , 0.001) were independent risk factors that affected the carotid IMT value in patients with LN. Conclusions: The prevalence of MS was comparatively high in patients with LN and was significantly correlated with carotid atherosclerosis, indicating that MS screening might be useful in the prevention and treatment of carotid atherosclerosis in patients with LN. Key Indexing Terms: Metabolic syndrome; Lupus nephritis; Atherosclerosis. [Am J Med Sci 2014;348(6):486–491.]
S
ystemic lupus erythematosus (SLE) is an autoimmune inflammatory disease involving multiple organs; twothirds to three-fourths of patients with SLE develop renal damage. Several studies reported that the prevalence and mortality rates of cardiovascular disease (CVD) in patients with lupus nephritis (LN) were significantly higher than in healthy persons.1,2 As immunosuppressive treatment gradually becomes more sophisticated, the mortality rate of acute-phase patients has decreased significantly, whereas CVD has become the main cause of death among patients with LN in the stable phase.3 Carotid artery ultrasound is a simple and reliable method used to detect subclinical atherosclerosis in the early stages. Carotid artery plaque and intima-media thickness (IMT) are easy to test noninvasively and thus can be used as windows to observe atherosclerosis development in the entire body.4 Recent studies have shown that metabolic syndrome (MS) is closely correlated with the occurrence and prognosis of CVD. Every component of MS is a risk factor of CVD occurrence, and a combination of multiple abnormalities occurring at the same time results in a higher CVD risk.5 Although a consensus has not been reached in terms of the exact definition of MS among different periods and academic From the Renal Division, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. Submitted March 4, 2014; accepted in revised form July 9, 2014. Supported by the Seed Research Program of Shanghai Renji Hospital. The authors have no financial or other conflicts of interest to disclose. Correspondence: Zhaohui Ni, MD, Renal Division, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai 200127, China (E-mail: [email protected]).
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organizations, the improved criteria of MS established by the International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute in 2009 are widely recognized by academia at present.6 The criteria state that a diagnosis can be made if either 3 of the following are present: central obesity, increased triglycerides (TG), decreased high-density lipoprotein cholesterol (HDL-C), increased blood pressure and increased fasting blood glucose (FBG). In the general population, as well as in adolescents and adults with hypertension, MS was previously reported to be correlated with carotid atherosclerosis.7–9 However, no relevant report was found in patients with LN. Hence, in this observational study, we performed carotid artery ultrasound on patients with LN and discussed its relevance in the prevalence of MS.
METHODS Study Subjects This was a single-center, cross-sectional study. Two hundred ten SLE patients with LN, who visited our hospital between January 2010 and October 2013, were selected as study subjects. The control group included 150 age-matched SLE patients without nephritis and 200 age-matched healthy persons. We referred to the diagnostic criteria for SLE classification established by the American Rheumatism Association.10,11 The exclusion criteria were as follows: (1) acute cardiovascular events (defined as acute coronary syndrome, new-onset arrhythmia, heart failure, cerebrovascular accident, peripheral vascular thrombosis or arterial dissection, etc.) occurring within a month before selection, (2) infection or trauma occurring within a month before selection, (3) tumors, (4) familial hyperlipidemia, (5) pregnancy or childbirth in women, (6) acute exacerbation of chronic renal failure and (7) dialysis or renal transplant. Disease activity was evaluated using the SLE disease activity index.12 Therapeutic exposures including corticosteroid, immunosuppressant and antimalarial drugs were recorded. All corticosteroid doses were converted to milligrams of prednisolone equivalent. The cumulative dose of prednisolone received from the beginning of treatment to enrollment (in grams) was calculated for each patient. The procedures followed in the study meet ethical requirements and were approved by the ethics committee of our hospital. All participants gave informed consent. Diagnostic Criteria of Metabolic Syndrome This study used the 2009 improved criteria of MS, which require meeting 3 or more of the following 5 components: (1) central obesity: waist circumference $90 cm in Chinese males and $80 cm in females (for a few patients without waist circumference data, body mass index [BMI] $25 kg/m2 was used instead), (2) increased TG: $150 mg/dL (1.7 mmol/L), or already receiving appropriate treatments, (3) decreased HDL-C: ,40 mg/dL (1.0 mmol/L) in males and ,50 mg/dL (1.3 mmol/L) in females, or already receiving appropriate treatments, (4) increased blood pressure: systolic blood pressure (SBP) $130 mm Hg, diastolic blood pressure (DBP) $85 mm Hg, already receiving appropriate
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MS and Carotid Atherosclerosis in Patients With LN
treatments or with a previous diagnosis of hypertension and (5) increased FBG: $100 mg/dL (5.6 mmol/L), a previous diagnosis of type 2 diabetes, or already receiving appropriate treatments. The “number of MS components” refers to the total number of aforementioned components in each patient, ranging from 0 to 5. Physical and Laboratory Examinations In all patients, blood pressure was measured in the morning, with the patient in the supine position after resting for at least 10 minutes. A mercury sphygmomanometer was used with the band wrapped on the left upper arm at the level of the heart. After blood pressure measurement, the height and weight of the patient were measured to calculate BMI. Waist circumference was measured from the front of the body, at the thinnest point between the ribs and the hipbone after exhalation. Fasting blood samples were drawn to test the following indices: hemoglobin, erythrocyte sedimentation rate, creatinine, urea nitrogen, uric acid, albumin, total cholesterol, TG, HDL-C, lowdensity lipoprotein cholesterol, FBG, calcium, phosphorus, complements C3 and C4, fibrinogen, high-sensitivity C-reactive protein (hs-CRP) and antibody test. hs-CRP was tested by using rate nephelometry (BNP nephelometer; Dade Behring, Deerfield, IL). The titer of serum antibodies against double-stranded DNA (ds-DNA) was determined by using radioimmunoassay (EUROIMMUN AG, Germany). Anti-nuclear antibody (ANA) was detected by using an indirect immunofluorescence method. Anti-cardiolipin antibody (ACL) was determined by using an enzyme-linked immunosorbent assay (EUROIMMUN AG, Leubeck, Germany). Twenty-four-hour urine samples were collected for quantitative examination of urinary proteins. Glomerular filtration rate (GFR) was calculated by using the following equation: 186 3 (Scr/88.4)21.154 3 age20.203 3 (0.742 if female).13 Carotid Artery Doppler Ultrasound Carotid artery ultrasound examinations were performed by professional sonographers at our hospital. The intervals between examination and blood sampling were controlled to be no more than 1 month. An HP-HX Color Doppler Ultrasound Diagnostic System (Hewlett-Packard Company, Palo Alto, CA) was used, with the transducer frequency at 10 MHz, the angle between ultrasonic beam and blood flow kept at ,60° and carotid artery IMT measured at 2 cm from the carotid bifurcation. IMT was defined as the distance from the interface between the tunica adventitia and media to the intimal surface. Atherosclerotic plaque was defined as local intima, that is, thicker than 1 mm and more than twice the thickness of the adjacent intima.14 Systolic peak velocity, diastolic velocity and resistance index were also measured. Statistical Methods Measurement data were expressed as mean 6 SD or median (interquartile range). Independent 2-sample t test was used to compare differences between 2 sets of data that are normally distributed. One-way analysis of variance was used to compare differences between multiple sets of data. MannWhitney’s U test was used to compare differences between 2 sets of data that are not normally distributed. A x2 test was used to compare differences in composition ratios. Pearson’s method was used for correlation analysis. Stepwise multiple linear regression was used to analyze the relation between 1 dependent variable and multiple independent variables. SPSS 19.0 software was used for statistical analysis. P , 0.05 was considered statistically significant. Ó 2014 Lippincott Williams & Wilkins
RESULTS Baseline Data The 210 patients with LN included 195 female patients (92.86%), and their average age was 38.83 6 12.41 years. Among them, 202 patients (96.19%) were ANA positive, 186 patients (88.57%) were ds-DNA positive and 40 patients (19.05%) were ACL antibody positive. One hundred fiftyeight patients (75.24%) had undergone renal biopsy; according to the 2003 LN classification by the International Society of Nephrology/Renal Pathology Society,15 there were 4 cases (2.53%) of minimal mesangial lesions (class I), 9 cases (5.70%) of mesangial proliferative lesions (class II), 21 cases (13.29%) of focal lesions (class III), 86 cases (54.43%) of diffuse lesions (class IV), 35 cases (22.15%) of membranous lesions (class V) and 3 cases (1.90%) of advanced sclerosis lesions (class VI). There was no significant difference regarding age and sex ratio among patients with LN, SLE patients without LN and healthy controls. The duration of disease and SLE disease activity index score were similar in SLE patients with LN and without LN. Prevalence of Carotid Artery Plaque Plaques were detected in 46 patients with LN (21.90%), 24 patients with SLE (16.00%) and 13 healthy controls (6.50%). The prevalence of carotid artery plaque was significantly higher in patients with LN compared with that in patients with SLE (P , 0.05) and healthy controls (P , 0.01). The patients with LN were divided into 2 groups according to the existence of carotid artery plaque. Compared with the nonplaque group, LN patients with plaques were older, had longer durations of disease, had higher BMI, had higher levels of SBP, FBG, TG, CRP and uric acid and had significantly decreased levels of hemoglobin and GFR. No significant difference was found regarding disease activity and medication between the 2 groups (Table 1). Prevalence of Metabolic Syndrome Eighty eight patients (41.90%) with LN, 46 patients (30.67%) with SLE and 23 (11.50%) healthy controls were diagnosed with MS. The prevalence of MS was significantly higher in patients with LN compared with that in patients with SLE (P , 0.05) and healthy controls (P , 0.01). The characteristics of LN patients with and those without MS were compared, and the results are shown in Table 2. LN patients with MS were older, had longer durations of disease, had higher BMI, waist circumference and cumulative dose of corticosteroid, had higher levels of SBP, DBP, CRP, FBG and TG and had lower levels of GFR and HDL-C. The sex ratios, albumin and urine protein levels, disease activity and positive rates of autoantibodies, including ds-DNA, ANA and ACL, showed no significant difference between the 2 groups. Correlation Between Metabolic Syndrome and Carotid Atherosclerosis in Patients With LN The carotid artery plaque ratio (28.41% versus 17.21%, P , 0.05) and IMT value (0.74 6 0.25 mm versus 0.64 6 0.18 mm, P , 0.01) were significantly elevated in LN patients with MS, as shown in Figure 1. In addition, as the number of MS components increased, the IMT value of the carotid artery in patients with LN showed a gradual upward trend (P , 0.01), as shown in Figure 2. In the univariate analysis, variables that were linearly correlated with carotid artery IMT, including age, duration of disease, BMI, SBP, FBG, TG, uric acid, CRP, GFR and cumulative dose of corticosteroid as well as the presence or absence of MS, were all included in stepwise
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TABLE 1. Comparison between LN patients with and without carotid artery plaque With plaque Without plaque (n 5 46) (n 5 164) Age, y 42.15 6 15.92 33.95 6 11.84a Gender, male, % 8.93 8.16 BMI, kg/m2 23.28 6 3.85 20.95 6 2.96b Waist circumference, 75.24 6 18.35 74.06 6 13.30 cm Smoke history, % 10.65 11.93 Duration of LN, mo 68.00 (17.00–108.00) 42.00 (19.25–70.75)a SBP, mm Hg 148.34 6 18.25 135.92 6 14.92b DBP, mm Hg 82.14 6 9.23 80.62 6 8.31 MABP, mm Hg 104.42 6 12.14 101.01 6 10.95b FBG, mmol/L 5.03 6 0.84 4.28 6 0.62b Hemoglobin, g/dL 96.62 6 22.99a 109.95 6 22.43b ESR, mm/h 58.00 (24.00–87.00) 47.00 (24.00–75.00) hs-CRP, mg/L 3.64 (2.03–5.84) 1.57 (0.89–2.38)a 21 GFR, mL$min $1.73 78.74 6 6.21 90.15 6 8.33a m22 Uric acid, umol/L 491.78 6 29.35 408.21 6 20.56b Calcium, mmol/L 2.08 6 0.28 2.06 6 0.24 Phosphate, mmol/L 1.29 6 0.37 1.25 6 0.22 TC, mmol/L 4.65 6 0.92 4.62 6 0.98 TG, mmol/L 1.66 (1.08–2.05) 1.42 (1.01–1.79)a LDL-C, mmol/L 2.59 6 0.88 2.71 6 0.86 HDL-C, mmol/L 1.14 6 0.32 1.28 6 0.41 Albumin, g/L 37.64 6 4.06 38.58 6 4.74 24-h urine protein, 3.48 6 2.91 3.07 6 2.52 g/24 h ds-DNA, % 89.54 88.40 ANA, % 95.94 97.25 ACL, % 19.86 18.32 Complement C3, g/L 0.64 (0.48–0.93) 0.58 (0.47–0.75) Fibrinogen, g/L 3.68 6 1.38 3.79 6 1.31 SLEDAI 4 (2–6) 5 (0–8) Medication Current use of CS, % 80.43 79.26 Current dose of CS, 5 (0–10) 8 (0–15) mg/d Cumulative dose of 12.25 (4.60–20.15) 8.80 (2.75–16.50) CS, g Immunosuppressant, % 34.78 31.70 Antimalarial, % 52.17 51.83 P , 0.01. P , 0.05. CS, corticosteroid; ESR, erythrocyte sedimentation rate; LDL-C, low-density lipoprotein cholesterol; MABP, mean arterial blood pressure; TC, total cholesterol. a b
multiple linear regression equation, and the results showed that age (b 5 0.026, P 5 0.033), duration of disease (b 5 0.057, P 5 0.025) and the presence of MS (b 5 0.074, P , 0.001) were independent risk factors that affected the carotid IMT value in patients with LN (Table 3).
DISCUSSION We found in our cross-sectional study that among patients with LN, those with MS had significantly increased carotid artery plaque ratio and IMT value, and that MS was an
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independent risk factor that affected the IMT levels of patients with LN. The independent correlation between MS and carotid atherosclerosis is consistent with the results of previous studies in normal populations, and the results of this study have expanded this claim to include the LN population. This is of great importance in clarifying the risk stratification for CVDs in patients with LN. Many studies have shown that the risk of CVD occurrence in patients with SLE is significantly higher than in healthy persons from the same age groups. In 1976, Urowitz et al16 proposed a bimodal mortality pattern: patients with early SLE mostly died of lupus activity and infection, whereas patients with late SLE mainly died of atherosclerosis-related diseases. Autopsy revealed that moderate to severe aortic, coronary, cerebral and renal atherosclerosis was present in 41% to 53% of patients with SLE.17 The reasons for atherosclerosis occurrence in patients with SLE are extremely complex. Conventional risk factors such as age, family history and smoking play important roles, yet cannot completely explain the increased CVD occurrence rate.18 SLE itself is a risk factor for atherosclerosis: various autoantibodies and sensitized lymphocytes against self-antigens existing in the bodies of patients with SLE facilitate the entrance of monocytes into blood vessel walls, which activate endothelial cells and cause the formation of atherosclerosis.19 It was previously reported that the longer the duration of SLE, the higher the possibility for the occurrence of CVD events.20 Our study also confirmed that patients with LN with long disease durations have a high occurrence rate of carotid atherosclerosis. Therapeutic exposure is another important reason for atherosclerosis in SLE duration. It is well known that long-term use of corticosteroids not only causes several metabolic disorders but also increases the risk of CVD. MS is a clinical syndrome that involves a combination of multiple metabolic diseases, including central obesity, hyperglycemia, dyslipidemia and hypertension. It is a combination of a group of metabolically correlated risk factors. This series of factors may directly promote the occurrence of atherosclerotic CVDs.21 In our study, the MS occurrence rate observed in patients with LN was 41.90%, which was significantly higher than that in patients with SLE and healthy controls. Compared with lupus patients without nephritis, LN is associated with more physiological and metabolic disturbances, including proteinuria, hypertension, dyslipidemia, insulin resistance and decreased GFR which are linked to increased risk of carotid atherosclerosis. Several hormonal, inflammatory and nutritional-metabolic factors may play key roles in MS development in kidney disease, such as raised proinflammatory cytokines, hyperactivation of the renin-angiotensin aldosterone system (RAAS), abnormal adipocytokine levels and poor vitamin D status.22 Obesity and insulin resistance are initiating factors of MS occurrence. The RISC study found through 3 years of followups that obesity is closely related with impaired insulin sensitivity and is independent of other variables.23 Furthermore, abdominal (visceral) obesity is a sign of insulin resistance. Our study found that the obesity index, BMI, in patients with LN of the MS group was significantly higher than that of the non-MS group, and the waist circumference value, which represents abdominal obesity, showed a significant difference. Since visceral fat cells metabolize more actively than subcutaneous fat cells, persons with abdominal obesity produce more free fatty acid, which causes lipid deposition in nonadipose tissues such as the liver and muscle. This will result in decreased insulin sensitivity in these tissues, which can trigger insulin resistance.24 Volume 348, Number 6, December 2014
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TABLE 2. Comparison between LN patients with and without MS With MS Without MS (n 5 88) (n 5 122) Age, y 41.39 6 10.83 35.72 6 12.05a Gender, male, % 8.75 8.85 BMI, kg/m2 23.84 6 4.25 20.37 6 3.14b Waist 77.48 6 16.28 71.96 6 15.98b circumference, cm Smoke history, % 11.23 10.77 Duration of LN, mo 65.00 (18.25–105.75) 44.00 (18.00–72.00)a SBP, mm Hg 150.37 6 20.21 132.75 6 16.89b DBP, mm Hg 87.28 6 11.29 79.52 6 9.93b MABP, mm Hg 109.84 6 15.36 102.74 6 12.80b FBG, mmol/L 4.87 6 0.72 4.14 6 0.66b Hemoglobin, g/dL 99.46 6 19.57b 102.76 6 21.82 ESR, mm/h 49.00 (26.00–90.00) 52.00 (21.00–78.00) hs-CRP, mg/L 3.47 (2.12–5.48) 1.66 (0.78–2.49)a 21 GFR, mL$min 79.62 6 7.46 88.65 6 9.05b $1.73 m22 Uric acid, umol/L 446.24 6 30.75 437.95 6 22.12 Calcium, mmol/L 2.03 6 0.19 2.07 6 0.21 Phosphate, mmol/L 1.21 6 0.28 1.28 6 0.23 TC, mmol/L 4.59 6 0.89 4.64 6 0.94 TG, mmol/L 1.63 (1.02–2.11) 1.44 (1.00–1.82)a LDL-C, mmol/L 2.69 6 0.82 2.61 6 0.67 HDL-C, mmol/L 1.01 6 0.23 1.31 6 0.38b Albumin, g/L 38.57 6 3.96 36.90 6 4.15 24-h urine 3.25 6 3.12 3.38 6 2.99 protein, g/24 h ds-DNA, % 87.35 89.93 ANA, % 97.25 95.81 ACL, % 17.96 19.02 Complement C3, g/L 0.59 (0.42–0.86) 0.60 (0.42–0.86) Fibrinogen, g/L 3.75 6 1.35 3.70 6 1.38 SLEDAI 5 (2–7) 4 (2–6) Medication Current use of CS, % 84.09 77.87 Current dose of CS, 10 (0–20) 5 (0–10) mg/d Cumulative dose of 16.50 (6.00–29.50) 7.25 (1.90–18.25)b CS, g Immunosuppressant, % 32.95 34.43 Antimalarial, % 46.59 53.28
FIGURE 1. Comparison of the carotid artery plaque ratio and IMT level between LN patients with and without MS. The carotid artery plaque ratio (28.41% versus 17.21%, P , 0.05) and IMT value (0.74 6 0.25 mm versus 0.64 6 0.18 mm, P , 0.01) were significantly elevated in LN patients with MS.
including adiponectin, resistin and leptin. Studies have revealed that in the presence of MS, metabolic disorders of these adipocytokines can all be involved in insulin resistance, dyslipidemia, abnormal glycometabolism, impaired vascular endothelial function and inflammatory reactions.26 Patients with MS show significantly decreased levels of adiponectin, which has antiinflammatory and antiatherosclerotic effects.27 Thus, obesity and insulin resistance both play important roles in the
P , 0.01. P , 0.05. CS, corticosteroid; ESR, erythrocyte sedimentation rate; LDL-C, low-density lipoprotein cholesterol; MABP, mean arterial blood pressure; TC, total cholesterol. a b
Compensatory hyperinsulinemia caused by insulin resistance can cause reduced antioxidant capacity and systemic inflammation.25 The results of our study indicate that the hsCRP level of patients with LN in the MS group was significantly higher than that of the non-MS group. Changes in the above-mentioned related indices will damage vascular endothelial cells and cause systemic arterial wall damage, which contributes to lipid deposition and causes the occurrence and development of atherosclerosis. In addition, adipose tissue is also an endocrine organ that secretes a series of adipocytokines, Ó 2014 Lippincott Williams & Wilkins
FIGURE 2. Correlation between the number of MS components and IMT level in patients with LN. As the number of MS components increased, the IMT value of the carotid artery in patients with LN showed a gradual upward trend (P , 0.01).
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TABLE 3. Risk factors that affect IMT level of carotid artery in patients with LN Determinants: IMT
Age log (duration of LN) MS
b
R2
P
0.026 0.057 0.074
0.119 0.226 0.194
0.033 0.025 ,0.001
Output from a multivariate stepwise regression model, which showed that MS was an independent marker for IMT. The original model included all variables significantly associated with IMT on univariate analysis, including age, duration of LN, BMI, SBP, FBG, TG, uric acid, CRP, GFR and cumulative dose of corticosteroid and the presence or absence of MS.
occurrence and development of atherosclerosis. Moreover, in the presence of MS, insulin resistance can cause hyperglycemia and increase the activity of the sympathetic nervous system, hinder endothelium-dependent nitric oxide synthesis and release, promote the proliferation of vascular smooth muscle cells, increase vascular resistance and trigger hypertension.28 In this study, LN patients with MS showed higher levels of SBP, DBP and FBG than patients without MS. Furthermore, IMT was positively correlated with SBP in patients with LN. Another important characteristic of metabolic disorder in patients with MS is dyslipidemia. The results of our study show that LN patients with MS have significantly higher TG levels than patients without MS, whereas their HDL-C levels are significantly lower than those of patients without MS. In the presence of MS, LDL particles rich in TG produced by the body become small and dense through lipolysis and can infiltrate more easily into the vessel wall and be oxidized, thus conferring stronger atherosclerotic promotion effects. Furthermore, HDL at low levels acquires a different composition, the core of which is rich in triacylglycerol and has a decreased level of cholesteryl ester, suggesting reduced antioxidant capacity and protective effect.29
CONCLUSIONS In conclusion, we found a correlation between MS and the degree of carotid atherosclerosis in patients with LN. Multiple intervention measures, including lifestyle modification, are recommended for this population to actively correct MS, in an attempt to prevent and control the occurrence and development of atherosclerosis.
ACKNOWLEDGMENTS The authors appreciated all the patients who voluntarily participated in this study. REFERENCES 1. Frostegård J. Systemic lupus erythematosus and cardiovascular disease. Lupus 2008;17:364–7. 2. Scalzi LV, Ballou SP, Park JY, et al. Cardiovascular disease risk awareness in systemic lupus erythematosus patients. Arthritis Rheum 2008;58:1458–64. 3. Gustafsson JT, Simard JF, Gunnarsson I, et al. Risk factors for cardiovascular mortality in patients with systemic lupus erythematosus, a prospective cohort study. Arthritis Res Ther 2012;14:R46.
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4. Nguyen-Thanh HT, Benzaquen BS. Screening for subclinical coronary artery disease measuring carotid intima media thickness. Am J Cardiol 2009;104:1383–8. 5. Wang J, Ruotsalainen S, Moilanen L, et al. The metabolic syndrome predicts cardio-vascular mortality: a 13-year follow-up study in elderly non-diabetic Finns. Eur Heart J 2007;28:857–64. 6. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120: 1640–5. 7. Iglseder B, Cip P, Malaimare L, et al. The metabolic syndrome is a stronger risk factor for early carotid atherosclerosis in women than in men. Stroke 2005;36:1212–7. 8. Reinehr T, Wunsch R, Pütter C, et al. Relationship between carotid intima-media thickness and metabolic syndrome in adolescents. J Pediatr 2013;163:327–32. 9. Cuspidi C, Sala C, Lonati L, et al. Metabolic syndrome, left ventricular hypertrophy and carotid atherosclerosis in hypertension: a genderbased study. Blood Press 2013;22:138–43. 10. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25:1271–7. 11. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725. 12. Bombardier C, Gladman DD, Urowitz MB, et al. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 1992;35:630–40. 13. Zuo L, Ma YC, Zhou YH, et al. Application of GFR-estimating equations in Chinese patients with chronic kidney disease. Am J Kidney Dis 2005;45:463–72. 14. Stompór T, Krasniak A, Su1owicz W, et al. Changes in common carotid artery intima-media thickness over 1 year in patients on peritoneal dialysis. Nephrol Dial Transpl 2005;20:404–12. 15. Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 2004;65:521–30. 16. Urowitz MB, Bookman AA, Koehler BE, et al. The bimodal mortality pattern of systemic lupus erythematosus. Am J Med 1976;60:221–5. 17. Bessant R, Hingorani A, Patel L, et al. Risk of coronary heart disease and stroke in a large British cohort of patients with systemic lupus erythematosus. Rheumatology (Oxford) 2004;43:924–9. 18. Bruce IN, Urowitz MB, Gladman DD, et al. Risk factors for coronary heart disease in women with systemic lupus erythematosus: the Toronto Risk Factor Study. Arthritis Rheum 2003;48:3159–67. 19. Gómez-Zumaquero JM, Tinahones FJ, De Ramón E, et al. Association of biological markers of activity of systemic lupus erythematosus with levels of anti-oxidized low-density lipoprotein antibodies. Rheumatology (Oxford) 2004;43:510–3. 20. Esdaile JM, Abrahamowicz M, Grodzicky T, et al. Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum 2001;44:2331–7. 21. Lionetti L, Mollica MP, Lombardi A, et al. From chronic overnutrition to insulin resistance: the role of fat-storing capacity and inflammation. Nutr Metab Cardiovasc Dis 2009;19:146–52. 22. Slee AD. Exploring metabolic dysfunction in chronic kidney disease. Nutr Metab (Lond) 2012;26:36.
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23. Bobbioni-Harsch E, Pataky Z, Makoundou V, et al. Fat distribution influences the cardio-metabolic profile in a clinically healthy European population. Eur J Clin Invest 2009;39:1055–64.
26. de Ferranti S, Mozaffarian D. The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences. Clin Chem 2008; 54:945–55.
24. Koska J, Stefan N, Permana PA, et al. Increased fat accumulation in liver may link insulin resistance with subcutaneous abdominal adipocyte enlargement, visceral adiposity, and hypoadiponectinemia in obese individuals. Am J Clin Nutr 2008;87:295–302.
27. Calton EK, Miller VS, Soares MJ. Factors determining the risk of the metabolic syndrome: is there a central role for adiponectin? Eur J Clin Nutr 2013;67:485–91.
25. Romeo GR, Lee J, Shoelson SE. Metabolic syndrome, insulin resistance, and roles of inflammation–mechanisms and therapeutic targets. Arterioscler Thromb Vasc Biol 2012;32:1771–6.
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28. Ferrannini E, Cushman WC. Diabetes and hypertension: the bad companions. Lancet 2012;380:601–10. 29. Franssen R, Monajemi H, Stroes ES, et al. Obesity and dyslipidemia. Med Clin North Am 2011;95:893–902.
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