Patients with systemic lupus erythematosus (SLE) are prone to accelerated atherosclerosis and arterial thromboembolism. Many of the traditional Framingham risk factors contribute to this, along with nontraditional lupus-related factors including antiphospholipid antibodies, hyperhomocysteinemia, lipid peroxidation, antioxidized low-density lipoprotein (LDL) antibodies, persistently elevated inflammatory cytokines, chronic renal insufficiency, and the long-term use of medications such as corticosteroids13. The incidence of subclinical atherosclerosis in the carotid and coronary vessels as detected by Doppler ultrasound and electron beam computed tomography (CT), respectively, is significantly higher in patients with SLE compared with age and sex-matched healthy controls1,15. The relative risk of arterial thrombosis such as acute myocardial infarction in SLE patients is significantly increased compared to the general population, especially in the 35-44 year age-group9. Moreover, the relative risks of arterial thrombosis such as myocardial infarction and ischemic stroke in SLE patients are significantly higher than those expected based on the Framingham models, indicating that traditional risk factors alone cannot fully explain the increased risk4.
Renal disease is a major manifestation of SLE. Nephritis is more common in certain ethnic groups, such as African-Americans, Hispanic Americans, and the Chinese2,10. A 2004 study showed that 60% of our Chinese patients with SLE developed overt renal involvement within the first 5 years of onset of the disease10. Despite aggressive immunosuppressive treatment, the 10-year renal survival rate of a large group of Chinese patients with diffuse proliferative lupus nephritis was 83%11. After a mean observation of 8.8 years after the diagnosis of lupus nephritis, 14% of the patients had doubling of serum creatinine level compared to baseline, and 8% of them developed end-stage renal failure.
Chronic renal dysfunction is another important contributing factor to accelerated atherosclerosis. This is in turn the result of an increased prevalence of traditional risk factors such as hypertension, dyslipidemia, and left ventricular hypertrophy, as well as uremia-related factors such as chronic albuminuria, anemia, hyperhomocysteinemia, oxidative stress, abnormal calcium/phosphate metabolism, malnutrition, and elevated levels of thrombogenic factors such as fibrinogen and inflammatory markers like C-reactive protein16. Thus, SLE patients with nephritis are more prone to arterial thromboembolic complications than those without renal involvement.
In a previous prospective cohort study, we reported a 5-year cumulative risk of arterial thrombotic event of 8.5% in 258 Chinese patients with new-onset SLE12. However, subgroup analysis on those with renal disease or renal insufficiency was not performed. In the current study, we identified those patients with lupus renal involvement from our cohort database and evaluated the cumulative risk of arterial thrombosis. We compared them with another group of patients with renal biopsy-confirmed nondiabetic primary glomerulonephritis. We constructed a multivariate model to detect the risk factors for arterial thrombotic events and to determine whether SLE itself contributed independently to the risk.
PATIENTS AND METHODS
Tuen Mun Hospital is a large regional public hospital in the western part of the New Territories, Hong Kong, that serves one million of the population residing in the vicinity. The Hospital Information Retrieval System (HIRS) is a computer system that records demographic data and clinical and laboratory findings of all patients who attend our hospital. This includes patients who are hospitalized and those who attend the outpatient specialty clinics. Coding for clinical procedures and new diagnoses by physicians is compulsory. Data can be retrieved by means of the diagnostic coding and the identity of patients.
Patients in whom SLE was diagnosed between 1993 and 2003 and who fulfilled at least 4 of the American College of Rheumatology criteria for the classification of SLE20 were identified from the cohort database maintained by the Division of Rheumatology of the Department of Medicine, Tuen Mun Hospital. This database includes research data in addition to the data provided by the HIRS. Among these patients, we included those with renal involvement according to the American College of Rheumatology criteria (persistent proteinuria ≥0.5 g/d, the presence of cellular casts, or histologic evidence of lupus glomerulonephritis) for further analysis20. Within the same time period, we also identified patients with primary glomerulonephritis from the renal biopsy registry, which is a part of the HIRS that records patients who have undergone renal biopsy. Those with diabetic nephropathy and hypertensive glomerulosclerosis or without a definite pathologic diagnosis were excluded from analysis.
Basic demographic data such as age, sex, and date of diagnosis of lupus or primary glomerulonephritis were collected from patients through the HIRS. Traditional risk factors for atherosclerosis such as smoking, obesity, dyslipidemia, diabetes mellitus, hypertension, and menopausal status were assessed. Data on the use of medications since the diagnosis of glomerulonephritis such as corticosteroids, cyclophosphamide (CYC), azathioprine (AZA), mycophenolate mofetil (MMF), calcineurin inhibitors (cyclosporin A and tacrolimus), hydroxychloroquine (HCQ), low-dose aspirin, statins, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin-receptor antagonists were also retrieved for analysis.
Patients with lupus and primary glomerulonephritis were followed by the same group of rheumatologists or nephrologists at 12-week intervals. More frequent follow-up was arranged for those with active disease, deteriorating renal function, or complications related to disease or treatment. The outcome of study was the development of arterial thromboembolic events in these 2 groups of patients. We noted the date of first occurrence of these events and calculated the cumulative risk with the Kaplan-Meier plot. We compared the 2 groups of patients, and constructed a multivariate model to evaluate the contribution of different demographic and traditional risk factors to arterial thrombosis and whether SLE itself was an independent predictor.
Definitions of Arterial Thromboembolic Events
Arterial thromboembolic events referred to signs and symptoms caused by partial or complete stenosis of major arteries. These included cerebrovascular accident (CVA or stroke), transient ischemic attack (TIA), angina pectoris, acute myocardial infarction, digital gangrene, intermittent claudication, amaurosis fugax, and retinal artery occlusion. These events were diagnosed and ascertained with the collaboration of the cardiologists and neurologists working in our unit based on symptoms, clinical signs, and investigations such as CT scan, magnetic resonance imaging (MRI), radionuclide heart perfusion scan, exercise stress test, and cardiac catheterization. Only new events since the diagnosis of glomerulonephritis were analyzed.
We compared categorical and continuous data of the 2 groups of patients by the chi-square and Student t-test, respectively. The cumulative probability of having arterial events over time was studied by the Kaplan-Meier plot, with time zero referring to the date of diagnosis of lupus renal disease or primary glomerulonephritis. Arterial events that occurred before the diagnosis of glomerulonephritis were excluded. For patients who died or were lost to follow-up, data were censored at their last clinic visits.
The following clinical variables were considered to be predictors of arterial events: age at onset of glomerulonephritis; male sex; traditional risk factors ever present since diagnosis for at least 2 years that included smoking, hypertension (blood pressure ≥130/85 mm Hg or requiring drug therapy), diabetes mellitus (fasting blood sugar ≥7.0 mmol or requiring drug therapy), obesity (body mass index ≥27 kg/m2), LDL cholesterol level ≥2.6 mmol/L (100 mg/dL), HDL cholesterol level ≤1.0 mmol/L (39 mg/dL), chronic renal insufficiency as defined by an estimated glomerular filtration rate (GFR) by the Modification of Diet in Renal Disease formula7 of less than 30 mL/min (that is, stage 4 and stage 5 chronic kidney disease according to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines14) within the first 3 years of diagnosis of glomerulonephritis; SLE; and use of high-dose prednisolone (defined as daily dose >0.8 mg/kg per d for >8 wk), AZA, CYC, MMF, calcineurin inhibitors, HCQ, aspirin, statins, ACE inhibitors, and angiotensin II-receptor blockers (ARB).
The risk of arterial thromboembolism between patients with lupus nephritis and primary glomerulonephritis was compared by the log-rank test. The Cox regression model was constructed for multivariate analysis of the predictors for arterial events. Each of the covariates mentioned above was first put in the regression equation separately, with the hazard ratios and 95% confidence intervals calculated. This was followed by a multivariate model with the inclusion of all potentially confounding covariates in the regression equation.
Statistical significance was defined as a p value of less than 0.05, 2-tailed. All statistical analyses were performed using the SPSS program, version 11.5 (SPSS, Chicago, IL) for Windows XP (Microsoft, Redmond, WA).
One hundred sixty-two patients with lupus nephritis (89% women) and 181 patients with primary glomerulonephritis (48% women) were studied. The mean age of patients at the diagnosis of lupus nephritis was 28.8 ± 12 years, while that of those with primary glomerulonephritis was 42.7 ± 16 years. Twenty-eight (17%) patients did not undergo renal biopsy for the following reasons: 1) renal parameters did not meet our biopsy criteria (22 patients); 2) patient's reluctance to have the procedure (3 patients); 3) the presence of contraindications for biopsy, such as severe thrombocytopenia (3 patients). The distribution of the histologic classes of lupus nephritis in those who had renal biopsy was as follows: diffuse proliferative lupus nephritis (54%), pure membranous nephritis (18%), focal proliferative nephritis (17%), mesangial lupus nephritis (7%), minimal change glomerulonephritis (1%), and inadequate number of glomeruli for diagnosis (2%). Correspondingly, the histologic diagnoses of the group of patients with primary glomerulonephritis were as follows: IgA nephropathy (28%), focal segmental glomerulosclerosis (18%), minimal change glomerulonephritis (16%), membranous glomerulonephropathy (14%), mesangial proliferative glomerulonephritis (8%), membranoproliferative (6%), chronic glomerulonephritis (3%), crescentic glomerulonephritis (2%), IgM nephropathy (1%), and other types of glomerulonephropathies (4%).
Vascular Risk Factors in Lupus and Non-Lupus Patients
Table 1 shows the demographic characteristics, traditional cardiovascular risk factors, and use of medications since the diagnosis of glomerulonephritis in the 2 groups of patients. More of the patients with primary glomerulonephritis were male, and the mean age was significantly greater compared with patients with lupus nephritis. Vascular risk factors such as smoking, hypertension, obesity, and renal dysfunction early in the course of the disease were significantly more common in the primary glomerulonephritis group of patients. Patients with primary glomerulonephritis were less likely to receive AZA, CYC, MMF, and HCQ for the treatment of renal disease and related manifestations, as well as long-term corticosteroids as maintenance therapy. However, the use of ACE inhibitors/ARB and statins was more frequent in that group than in the lupus group. Prophylactic use of aspirin for primary prevention of arterial thrombosis was not common in patients with lupus nephritis (4%). For patients with primary glomerulonephritis, the use of aspirin was similarly uncommon (7%), and mainly because of previous vascular events before the diagnosis of the renal disease. None of our patients had received anticoagulation before the occurrence of thrombotic events.
Risk Factors for Arterial Thromboembolism in Lupus and Non-Lupus Glomerulonephritis
Table 2 shows the risk factors and univariate hazard ratios for arterial thrombosis in lupus and non-lupus patients. Smoking, hypertension, diabetes mellitus, increasing age, and uremia were significant predictors of arterial events in patients with non-lupus primary glomerulonephritis. In contrast, only hypertension and LDL hypercholesterolemia were significant risk factors for arterial thrombosis in patients with lupus nephritis.
Incidence and Cumulative Risk of Arterial Thromboembolism
After a total of 2783 patient-years of follow-up (mean, 8.1 yr), 47 (14%) patients died, 23 (7%) were lost to follow-up, and 38 (11%) developed 42 arterial events (incidence, 15.1/1000 patient-years; 60% stroke/TIA, 21% myocardial infarction/angina, 14% retinal artery thrombosis/amaurosis fugax, 5% digital embolism/peripheral vascular disease). The incidence and nature of the arterial events in patients with lupus and non-lupus glomerulonephritis is shown in Table 3. The incidence of cerebrovascular and cardiovascular events was similar in the 2 groups of patients. More patients with lupus nephritis had retinal artery thrombosis, but the difference was not statistically significant.
Figure 1 shows the cumulative probability of having an arterial event for patients with lupus nephritis and those with primary glomerulonephritis. The risk of an arterial event at 5 years after diagnosis in patients with lupus nephritis was 6.3%, which was not significantly different from that for patients with primary non-lupus glomerulonephritis (6.6%; p = 0.96 by log-rank test). At 10 years after diagnosis of renal disease, there was a trend of higher incidence of arterial thrombotic events in the SLE group.
Effect of Lupus on the Risk of Arterial Thromboembolism
Table 4 shows the results of statistical analyses of the risk factors for arterial events in all patients studied. Univariate analysis revealed that increasing age, smoking, diabetes mellitus, hypertension, LDL-hyperlipidemia, and renal dysfunction were significant risk factors for arterial events. In a multivariate Cox regression model, SLE was demonstrated to be an independent risk factor for arterial thromboembolism, after adjustment for demographic variables and traditional risk factors (hazard ratio 3.57 [1.07-11.9]; p = 0.04). Other significant independent risk factors identified in this model were increasing age (hazard ratio 1.04 [1.01-1.07] per year; p = 0.02), LDL-hyperlipidemia (≥2.6 mmol/L; hazard ratio 4.46 [1.71-11.6]; p = 0.002), and renal insufficiency (GFR <30 mL/min; hazard ratio 2.67 [1.05-6.83]; p = 0.04). A repeat analysis (data not shown) on those SLE patients with renal biopsy (n = 134) and patients with primary glomerulonephritis (n = 181) yielded essentially similar results: SLE (hazard ratio 4.23 [1.25-14.4]; p = 0.02), increasing age (hazard ratio 1.05 [1.01-1.08] per year; p = 0.008), renal insufficiency (hazard ratio 2.79 [1.10-7.10]; p = 0.03), and LDL-hyperlipidemia (hazard ratio 3.71 [1.39-9.95]; p = 0.009) remained independent risk factors for arterial thrombosis.
Risk of Arterial Thromboembolism As a Function of Early Renal Damage
We stratified all patients into 3 groups according to the estimated GFR 3 years after the diagnosis of glomerulonephritis: 1) Group 1: GFR >90 mL/min (stage 1 chronic kidney disease according to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines13); 2) Group 2: GFR 30-89 mL/min (stage 2 and 3 chronic kidney disease); 3) Group 3: GFR <30 mL/min (stage 4 and 5 chronic kidney disease). The cumulative risk of having an arterial thrombotic event at 10 years after the diagnosis of renal disease was 6.9% in Group 1 patients, 9.9% in Group 2 patients, and 22.0% in Group 3 patients. The trend of increase in incidence of arterial thrombosis with declining renal function early in the course of the disease was statistically significant (p < 0.001).
Effect of Antiphospholipid Antibodies on Risk of Arterial Thrombosis
Data on antiphospholipid antibodies were available only for patients with lupus nephritis, as these tests were not routine for non-lupus patients. Sixty-two (38%) of our patients with lupus nephritis were either positive for anticardiolipin antibodies (IgG) or lupus anticoagulant. In a separate multivariate model involving patients with lupus nephritis only (data not shown), the presence of antiphospholipid antibodies was not a significant risk factor for arterial thrombosis (hazard ratio 2.59 [0.71-9.47]; p = 0.15). The cumulative 10-year risk of arterial thrombosis in patients with positive antiphospholipid antibodies was numerically higher than that of patients without antiphospholipid antibodies (19.6% vs. 10.4%; p = 0.12 by log-rank test), but the difference was not statistically significant.
We report here a comparative study of the risk of arterial thromboembolism in patients with lupus glomerulonephritis and patients with non-lupus primary glomerulonephritis. We demonstrated that the cumulative incidence of arterial thrombotic events in lupus and non-lupus patients was 6.3% and 6.6%, respectively, at 5 years after diagnosis. Despite a significantly younger age and lower frequency of cardiovascular risk factors such as male sex, smoking, hypertension, obesity, and renal insufficiency, the risk of thrombosis in lupus patients was not significantly lower than that in non-lupus patients. This suggests that some intrinsic lupus-related factors are associated with arterial thrombosis. In fact, in the multivariate regression model, we were able to demonstrate that SLE itself was an independent predictor for the occurrence of arterial thromboembolism in all patients studied. Moreover, early renal damage (defined as an estimated GFR <30 mL/min at 3 years after diagnosis of glomerulonephritis) was another independent risk factor for arterial thrombosis in the long run in all the patients studied.
In addition, we demonstrated that the absolute incidence of myocardial infarction and cerebrovascular accident was higher in patients with primary glomerulonephritis than that in patients with lupus nephritis. This can be partially explained by the fact that SLE patients were generally younger. On the other hand, amaurosis fugax and retinal artery thrombosis occurred exclusively in patients with lupus nephritis. The reason for this remains obscure. One possible contributing factor is that SLE patients who were treated with long-term hydroxychloroquine (36% of our patients) were referred for routine ophthalmologic surveillance in our unit, and subtle retinal artery abnormalities might be more likely to be detected by the ophthalmologists.
SLE is a prototype of autoimmune disease characterized by a myriad of autoantibodies and elevation of serum inflammatory cytokines especially during disease activity. A number of inflammatory mediators and autoantibodies such as interleukin-6, CD40/CD40L, adhesion molecules, antiphospholipid, antioxidized LDL, anti-heat shock protein antibodies, plasminogen activator inhibitor-1, and homocysteine are implicated in accelerating the development of atherosclerosis18. Moreover, chronic renal insufficiency and the long-term use of medications such as corticosteroids may also contribute to atherosclerosis. Indeed, a number of recent case-control studies have reported that subclinical atherosclerosis in the major vessels are significantly more common in patients with SLE1,15. The observed incidence of arterial thromboembolism cannot be accounted for by the presence of traditional risk factors alone4. The current study clearly shows that for patients with immune-mediated glomerulonephritis, the presence of SLE itself is an independent risk factor for arterial thrombosis. One of the possible nontraditional factors involved in the increased thrombogenicity of SLE is antiphospholipid antibodies. Because we lacked data on antiphospholipid antibodies in non-lupus patients, we were unable to analyze the effect of these antibodies on thrombotic risk in all patients. However, in patients with lupus nephritis, there was a trend of an increase in the risk of arterial thrombosis with the presence of antiphospholipid antibodies. The failure to demonstrate antiphospholipid antibodies as a significant thrombotic risk factor may be related to the relatively small sample size of patients and the limited number of arterial events.
End-stage renal failure, or uremia, is a major risk factor for accelerated atherosclerosis and arterial thrombosis. The incidence of cardiovascular disease and mortality is increased more than twofold in nondiabetic patients with chronic kidney disease when compared to those without evidence of chronic kidney disease5. In high-risk patients with cardiovascular disease or cardiovascular risk factors, a lesser degree of renal insufficiency is also an independent factor for adverse outcomes of cardiovascular disease17,22. However, whether renal insufficiency is an independent risk factor for arterial thrombosis in unselected community-based populations is less consistent3,6,8. The discrepancy is possibly related to the insufficient power of some studies to examine subgroup relationships. A 2004 pooled analysis of more than 20,000 subjects revealed that chronic kidney disease was an independent risk factor for cardiovascular disease and all-cause mortality in the general population, even after adjustment for the black race and other confounding factors21. In the current study, we demonstrated that chronic renal insufficiency was an independent risk factor for arterial thrombosis in patients with glomerulonephritis. After adjustment for demographic factors, traditional risk factors, and the chronic use of various medications, the hazard ratio of renal damage (estimated GFR <30 mL/min within 3 yr of diagnosis) for arterial events was 2.67. This is consistent with results of a recent analysis from our group showing that SLE patients who underwent continuous ambulatory peritoneal dialysis for end-stage renal failure as a result of glomerulonephritis had significantly more cardiovascular events and mortality compared with nondiabetic patients with primary idiopathic glomerulonephritis19.
In conclusion, the current long-term observational study shows that in patients with nondiabetic immune-mediated glomerulonephritis, the cumulative risk of arterial thrombosis at 5 years after diagnosis is around 6%. In addition to increasing age, dyslipidemia, and uremia, SLE itself is an independent risk factor for the development of arterial thrombosis. Thus, more vigorous preventive strategies for arterial thrombosis, in addition to control of traditional risk factors, seem to be justified in patients with lupus glomerulonephritis.
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