In this study, we found that pediatric patients who initiated HD when ≤ 18 years of age with ESRD secondary to SLE are at an almost 2-fold higher risk of death compared with pediatric patients with ESRD secondary to other causes. Strikingly, there was no significant difference in the risk of death between pediatric and adult patients with SLE, indicating that the pediatric population with SLE is at significant risk. In both pediatric and adult patients with SLE, the vast majority of the deaths were secondary to cardiovascular disease.
In adults with chronic inflammatory rheumatic conditions such as SLE and rheumatoid arthritis, numerous reports have shown an increased incidence of cardiovascular events compared with age-matched normal controls [11
]. In women with SLE aged 35–55 years, the incidence of myocardial infarction was 50 times higher than for normal controls. This increased risk of cardiovascular events is not explained by traditional risk factors such as hypertension, diabetes, or smoking [13
In a series of 31 children with SLE, 16% of them had abnormalities in cardiac perfusion on thallium perfusion scans [14
]. In a cohort of 221 pediatric patients with SLE, proteinuria was associated with increased carotid wall intima media thickness [15
]. Some studies have shown increased markers for subclinical atherosclerosis in young adults with SLE and it is hypothesized that the atherosclerotic process begins earlier in children with chronic inflammatory diseases [16
Inflammation may play a pathological role in the development of cardiovascular disease. Serum markers of inflammation such as C-reactive protein and tumor necrosis factor-α have been shown to mediate the development of atherosclerosis [17
]. The amount of inflammation in adult patients with SLE has been shown to correlate with increased carotid intima-media thickness, a surrogate of subclinical atherosclerosis [16
]. In addition, increased disease activity and damage scores in adults with SLE correlate with atherosclerosis [23
]. In the USRDS dataset, there is no information on disease activity indices or inflammatory markers; thus, we are not able to correlate the degree of inflammation with cardiovascular disease. However, an increased inflammatory state leading to atherosclerosis may account for the much younger age at death for the adult patients with ESRD secondary to SLE compared with other patients.
As regards more traditional risk factors, elevated triglyceride and very-low-density lipoprotein (VLDL) have been found in both pediatric and adult patients with SLE [24
]. Additionally, increased low-density lipoprotein (LDL) oxidation has been found in pediatric patients with SLE [25
]. In patients with ESRD secondary to other causes, dyslipidemia may also occur [27
]. Markedly increased triglyceride levels and small dense LDL particles have been reported in patients receiving hemodialysis. However, there is less of an association between LDL levels and the presence of cardiovascular disease in patients receiving long-term hemodialysis compared with the general population. Medications used to treat SLE, such as glucocorticoids, may also contribute to lipid dysregulation [24
]. Hypertension, another traditional risk factor for atherosclerosis, has been seen in up to 60% of adults with SLE who are 10 years from their initial diagnosis [29
Guidelines have been developed to help diagnosis and treat these traditional risk factors in patients with SLE [30
]. These include counseling on regular exercise and diet to maintain a BMI <25 kg/m2
, treating dyslipidemia with a goal LDL of < 100 mg/dl, checking blood pressure at each visit and between visits for those on corticosteroid therapy, tobacco cessation, and monitoring yearly fasting glucose. It is unclear if checking C-reactive protein as a marker for inflammatory cardiovascular risk in patients with SLE is helpful as it can be elevated in patients with active disease.
For patients with renal disease secondary to SLE, nephrotic range proteinuria has been associated with increased carotid intimal wall thickness in pediatric patients with SLE. Nephritis can also be associated with hypertension, which may be a contributor to atherosclerosis in some of these patients [4
This study is limited by the retrospective nature of the data. Detection of incident cases of ESRD in the USRDS is not complete because data from patients who die of ESRD before receiving renal replacement therapy is not included. This may dilute the hazard ratio as the sickest patients would not be included in the analysis. Pediatric patients with SLE were older than patients with other causes of ESRD at first entry into the USRDS database. This may be because SLE presents later in adolescence, usually after puberty, whereas other causes of ESRD in the pediatric population, such as urological disease, present in early childhood. This age difference may be why pediatric patients with SLE were older at death. Interestingly, even after adjusting for this difference in age, mortality was higher in pediatric patients with SLE suggesting that the disease itself, either through inflammation or mechanisms not yet known, may increase mortality.
Our study demonstrates that there is a significant increase in mortality, particularly secondary to cardiovascular disease, in pediatric and adult patients with ESRD secondary to SLE compared with other patients with ESRD. This is especially true for pediatric patients with SLE who began HD on or before age 18 years, where the risk of death was 2-fold higher than their peers. This suggests that pediatric and adult patients with ESRD secondary to SLE need careful monitoring and aggressive treatment for traditional risk factors for atherosclerosis such as hypertension and obesity. Additionally, they should also be evaluated for more non-traditional risk factors, which could result in an inflammatory state and contribute to cardiovascular disease. However, based on this study, it seems possible that the diagnosis of SLE alone may be an independent risk factor for death in patients with ESRD.