The main finding of this current study was that SUA levels are independently associated with CAD severity assessed by coronary angiography in patients who had mild-to-moderate CKD. A novel inflammatory marker, pentraxin-3, was also found to be associated with severity of CAD even after adjustment for traditional CAD risk factors.
Uric acid had long been considered as a strong antioxidant [20
]. However, recent experimental studies have challenged this view and have shown that uric acid behaves as a prooxidative agent, especially within the cells and under ischemic and hypoxic conditions [21
]. Clinical and epidemiologic studies have also provided increasing evidence that uric acid may have a contributory causal role in a number of disease states including hypertension and kidney disease [14
The association of elevated SUA with development of atherosclerosis has been the matter of numerous studies to date. Cardiovascular clinical outcomes and extent of atherosclerotic plaques have been two major end points used in numerous studies in this field to date. After the early work of Allard and Goulet [29
], which refuted an association between SUA levels and angiographically proven CAD severity, a number of subsequent investigations [30
] suggested a positive independent association, while others did not [34
]. Differences in studied populations, study protocols and methods to detect CAD (electron beam CT, coronary angiography) as well as lack of adjustment for inflammatory markers and other novel cardiovascular risk factors may in part account for discrepancies in the results of these studies. A previous meta-analysis reported by Wheeler et al. [37
] did not find an independent association of SUA levels with cardiovascular end points. However, a more recent meta-analysis comprising a larger number of randomized controlled studies showed that hyperuricemia may marginally increase the risk of CAD events, independently of traditional CAD risk factors [11
Few studies have examined the relationship of uric acid with cardiovascular disease in patients with CKD. Madero et al. [17
] evaluated the relationship of baseline uric acid with all-cause and cardiovascular mortality in 880 subjects from the Modification of Diet in Renal Disease (MDRD) study. Subjects had a mean eGFR of 33 ml/min/1.73 m2
and were followed for a median period of 10 years. Both all-cause and cardiovascular mortality were independently associated with baseline uric acid levels, with every 1-mg/dl increase of uric acid translating to 17 and 16% increase in mortality, respectively. More recently, a randomized trial was conducted in which allopurinol was administered for 2 years to 113 subjects with CKD (eGFR <60 ml/min/1.73 m2
). In this study, eGFR improved, CRP levels fell and cardiovascular events were reduced in the allopurinol arm [16
This current study provides additional evidence for a relationship of uric acid with coronary angiographic evidence for CAD in a CKD population. This is important, as cardiovascular death in CKD may represent electrolyte-induced arrhythmias or other causes besides CAD. If uric acid does have a causal role in CAD, it might be by its ability to stimulate the production of oxidized lipids [22
] or stimulate inflammation [10
]. Uric acid released from injured cells constitutes a major endogenous danger signal that activates the NALP3 inflammasome, which is important in inflammatory lung injury, leading to IL-1β production [39
]. Kono et al. [40
] also confirmed the role of uric acid as a proinflammatory molecule released from dying cells. Uric acid can also activate MAP kinases as well as nuclear transcription factors associated with the inflammatory response in a variety of cell types [10
]. Uric acid has also been demonstrated in atherosclerotic plaque [42
]. Uric acid is also known to induce small vessel disease in the kidney [43
]. The observation that a high uric acid is associated with low coronary blood flow [44
], and that a low uric acid is associated with greater coronary flow reserve and hyperemic mean flow velocity in normal subjects, would also be consistent with this possibility [45
]. Thus, uric acid may be a harbinger of smoldering inflammation in patients with ischemia or reduced eGFR, and is also independently associated with CAD in the CKD population.
Despite a well-established role in risk stratification in CAD, few studies incorporated inflammatory markers when evaluating association of SUA and CAD burden. Kocaman et al. [32
] demonstrated that the number of blood neutrophils and monocytes were independently related with SUA. In the Bezafibrate Infarction Prevention study [46
], the combined assessment of SUA and CRP levels provided incremental information for risk stratification of patients with CAD more than each parameter offered alone.
Pentraxin-3 is the prototypic long pentraxin. Both resident and innate immunity cells produce pentraxin-3 in peripheral tissues in response to inflammatory signals and Toll-like receptor activation [47
]. Pentraxin-3 is secreted at the site of tissue injury, in contrast to CRP which is secreted by the liver, the vasculature, and by mononuclear cells, and therefore may represent a better measure of the extent of local injury than CRP. In a cohort of 748 patients with ST elevation myocardial infarction, pentraxin-3, measured within the first day from the onset of symptoms along with established markers including CRP, NT-proBNP and troponin T, emerged as the only independent predictor of 3-month mortality [8
]. Rolph et al. [48
] also showed that advanced atherosclerotic plaques produced pentraxin-3. This group speculated that increased levels of pentraxin-3 in subjects with cardiovascular disease could reflect a protective physiologic response that correlates with the severity of the disease.
Persistent inflammation and oxidative stress start early in the process of CKD [49
]. Numerous studies have shown that elevated CRP predicts all-cause and cardiovascular mortality in CKD patients [50
]. Pentraxin-3 levels are increased in patients with CKD when compared to healthy controls [51
]. Plasma pentraxin-3 levels were also found to be increased in stage 3–4 and stage 5 CKD patients and were associated with the presence of cardiovascular disease and all-cause mortality [52
Our results demonstrated an association of serum CRP levels with Gensini scores. However, in contrast to pentraxin-3, the association of CRP with Gensini scores disappeared after controlling for traditional cardiovascular risk factors. This suggests that pentraxin-3 may be superior to CRP as an independent predictor of underlying atherosclerosis in subjects with CKD.
This study has several limitations. First, our study was cross-sectional and therefore conclusions regarding causality are not possible. Second, pentraxin-3, CRP and uric acid were measured only once during the course of the study. The levels of these molecules may change over time in a given person. Thus, it would be more appropriate to evaluate a number of measurements over a given time course. Despite these limitations, our study has strengths as well; we had a sufficient number of patients, and quantified severity of the atherosclerosis with the current gold standard, coronary angiography.
In conclusion, increased SUA and pentraxin-3 levels are independent determinants of the severity of CAD assessed invasively in patients with mild CKD. These studies raise the possibility that pentraxin-3 and uric acid may represent important nontraditional risk factors for CAD in the patient with CKD. Large trials aimed at lowering SUA and pentraxin-3 levels should be performed to determine if such treatments slow or halt the progression of atherosclerosis.